This chapter examines those conditions distinguished by damage to the intrahepatic bile ducts, in particular the interlobular and septal bile ducts, those small ducts typically seen in biopsy specimens. Bile duct injury, customarily manifest by epithelial alterations and ductal-centered inflammation, constitutes a feature of numerous disorders (Table 5-1). In many of these, the duct damage is an secondary histologic feature, inconstant and generally reversible. In other conditions, however, the ducts are progressively destroyed and eventually disappear. This results in chronic cholestasis, periportal inflammation and fibrosis, and ultimately evolves to biliary cirrhosis. Therefore, finding a diminished numbers of bile ducts -- also referred to as ductopenia -- is an important histologic observation, directing attention to a select group of disorders and narrowing the pathologist's differential diagnosis.^1,69,101

Recognizing a reduction in bile duct numbers depends upon an appreciation of the normal topographic relationship between ducts and hepatic artery branches in portal tracts: these two structures travel in parallel, and normally 70% to 80% of all interlobular arteries are associated with a bile duct of approximately similar size (Figure 5-1). When fewer than half the arteries are accompanied by ducts, paucity of bile ducts is clearly established (Figure 5-2).⁸⁰ An alternate but comparable criterion requires that 50% or more of the portal tracts be devoid of bile ducts as opposed to the 10% to 15% normally found.^39,216 Obviously any assessment of bile duct numbers assumes a biopsy of adequate size. A requirement of at least 20 portal tracts has been proposed, but most needle biopsy specimens will not satisfy that standard. Nevertheless, a careful inspection for bile duct changes will generally enable duct loss to be suspected even if not unequivocally verified. Further histologic features are then helpful in arriving at a more specific diagnosis, but needless to say, clinical and radiographic data are usually required for a definitive answer.

Acute cholangitis, in a morphologic sense, denotes active injury and acute inflammation of the bile ducts. This process may result from several types of biliary injury, although the foremost cause is bacterial infection. Indeed, this is the usual connotation when acute cholangitis is used as a clinical term.

Histologically, acute cholangitis is recognized by infiltration of the bile duct by neutrophils, specifically with invasion of ductal epithelium and, in severe cases, accumulation within the lumen to form intraductal microabscesses (Figure 5-3). The epithelium of the affected duct displays degenerative or reactive changes with enlarged nuclei and cytoplasmic basophilia; epithelial erosions or ulcerations may result. Neutrophils are also found in the connective tissue of involved portal tracts, often collecting around the bile duct.

Acute cholangitis should be distinguished from the inflammatory reaction commonly associated with proliferated bile ductules. This distinction is made by assessing the nature of the involved biliary structure: the interlobular bile ducts affected in acute cholangitis are closely allied with comparably-sized hepatic arteries whereas bile ductules are typically small, irregular, and unaccompanied by an arterial branch (Figure 5-4). Although neutrophils are regularly found in and around proliferated ductules, this is a nonspecific reaction seen in many types of hepatic injury and therefore lacks great diagnostic significance.¹ In addition, neutrophils are found in portal tracts, sometimes with a periductal distribution, in many conditions including uncomplicated cholelithiasis and acute cholecystitis;¹⁰ although not diagnostic of acute cholangitis, this pattern should prompt a careful search for active duct inflammation. Bacterial Cholangitis

Most acute cholangitis results from a bacterial infection superimposed on biliary obstruction. This obstruction may be produced by any of its varied causes (Chapter 4). Choledocholithiasis and biliary strictures are frequent offenders, but malignant neoplasms and congenital biliary anomalies such as choledochal cysts or Caroli's disease also contribute in some series of cases.^2,11,23,36

Although the complete pathogenetic story of bacterial cholangitis is not understood, the crucial factor is mechanical blockage of the biliary tract. By impeding bile flow, this blockage encourages bacterial growth, primarily by those organisms found in normal intestinal flora such as enteric gram-negative bacilli (including E. coli, Klebsiella, and Proteus), enterococci, and various anaerobic species. Precisely how these bacteria travel from bowel to bile is unclear; an obvious route is direct spread from the duodenum -- thereby accounting for the synonym ascending cholangitis -- but secondary involvement via the portal venous blood, gastrointestinal lymphatics, or an infected gallbladder represent other possibilities.^27,34 Moreover, organisms may be directly inoculated into the bile during invasive biliary tract procedures such as cholangiography; preexisting biliary obstruction is usually required for bacterial cholangitis to result.

Duct obstruction, in addition to promoting biliary infection, also increases intraluminal pressure. This pressure drives biliary bacteria into the blood, yielding positive blood cultures in 40% to 50% of patients.⁸ Systemic manifestations of sepsis follow; these can rapidly and dramatically resolve once the obstruction is relieved and the intraluminal pressure decreased.

Clinical Features. The clinical presentation of bacterial cholangitis is classically described by Charcot's triad -- fever and chills, jaundice, and abdominal pain. Unfortunately this triad is not invariable, since all three features are present in only 60% to 70% of patients.^2,36 The severity and course of these symptoms range across a wide spectrum. Many patients suffer a mild intermittent illness that quickly responds to antibiotic therapy and may even spontaneously resolve. Other patients, however, develop a severe fulminating disease additionally heralded by hypotension and mental status alterations. This extreme form of bacterial cholangitis -- imprecisely referred to as suppurative cholangitis -- may lead to septic shock and death; it requires urgent decompression of the biliary tract.^11,22,36

Pathologic Features. The histologic hallmark of bacterial cholangitis is acute cholangitis, typified by neutrophils among epithelial cells or within the duct lumen. In mild examples these changes can be subtle: intraepithelial neutrophils may be sparse and found in only an occasional bile duct, particularly within the smaller portal tracts. With severe disease marked ductal suppuration can be seen; uncommonly the duct is destroyed or hepatic abscesses develop.

Not unexpectedly, the background changes are those of biliary obstruction (Chapter 4). Portal tracts are enlarged, edematous, and infiltrated by neutrophils; bile ductular proliferation is prominent especially around the margins of the tract (Figure 5-5). Canalicular cholestasis is a variable finding and can be minimal or absent. In severe disease evidence of sepsis may appear: neutrophils accumulate in the sinusoids, sometimes forming lobular microabscesses.³³ Persistent or recurrent episodes of bacterial cholangitis are associated with features of chronic biliary obstruction, including lamellar periductal fibrosis, increasing mononuclear inflammation of portal tracts, and biliary fibrosis with portal-portal fibrous septa. Obstructive biliary cirrhosis is an infrequent late sequel.

Acute cholangitis is a useful but infrequent indicator of biliary obstruction, and although occasionally noted with uncomplicated duct blockage, it usually implies bacterial cholangitis. The histologic features, however, only approximately correlate with the clinical picture. Some patients with obvious acute cholangitis on liver biopsy lack the typical symptoms of bacterial cholangitis; conversely, histologic features may be missing or deceptively minimal when biliary infection is clearly evident clinically, presumably because the infectious process has not extended peripherally enough to affect the ducts seen in liver biopsies. Nonetheless, as a rule, cases with clinical cholangitis display more striking acute cholangitis.²⁴

Recurrent pyogenic cholangitis represents a singular type of bacterial cholangitis distinguished by its association with intrahepatic pigment stones and its predilection for Asian populations. The term hepatolithiasis is essentially a synonym, emphasizing the presence of the intrahepatic calculi rather than the episodic cholangitic course. This disorder is found throughout the Pacific coastal regions from Japan to Indonesia, but is particularly common in southeast Asia, notably Taiwan, Hong Kong, and southern China, where it constitutes a major biliary disease.^20,21,37 With a few exceptions, cases identified in Western countries occur in immigrants from these locales.³

Although the cause is unknown, many features of this condition originate from bile stasis. In turn, bile stasis promotes bacterial colonization and pigment stone formation, which are themselves mutually reinforcing: bacterial growth fosters pigment stone formation and, conversely, stones encourage bacterial growth.^7,20,37 A vicious pathogenetic cycle is thereby established, but the early inciting events nonetheless remain obscure. Suggested casual factors include biliary parasites and poor nutrition.^7,32 Although many patients harbor parasites such as Clonorchis sinensis, this is an inconstant finding and perhaps only signifies the frequency of endemic infection in the Far East.^7,37 A low-protein diet can predispose to biliary sludge formation and conceivably induce bile stasis, but unfortunately this does not explain the curious geographic distribution of the disease.

Clinical Features. Patients suffer recurring attacks of clinical cholangitis with abdominal pain, jaundice, fever, and chills. These episodes typically begin during the third or fourth decades, but the age range is wide and even children may be afflicted.^30,37 Severe cases may be complicated by sepsis, peritonitis, or portal vein thrombosis. However, some patients remain asymptomatic and are identified only when intrahepatic stones are discovered incidentally or at autopsy.^25,31 The pathogenetic implications of these differing clinical presentations are unknown.

The diagnosis of recurrent pyogenic cholangitis is generally suggested by the clinical setting and bolstered by radiographic imaging studies, including ultrasonography, computed tomography, and direct cholangiography, that demonstrate the characteristic intrahepatic stones and ductal changes.^5,9,14 Treatment involves appropriate antibiotics for acute attacks together with definitive biliary decompression by such procedures as transduodenal sphincteroplasty, bilioenteric anastomosis, or hepaticojejunostomy; for advanced disease, hepatic segmentectomy or lobectomy may be required.^3,28,37

Pathologic Features. The pathologic features reflect the consequences of repetitive bacterial infection and biliary stone formation. The large intrahepatic bile ducts, particularly the left hepatic duct, are affected early and demonstrate the most severe changes, but the extrahepatic ducts are eventually involved as well.^5,14 These major ducts are irregularly dilated and stenotic with patchy scarring and thickening of their walls. Active ductal suppuration is frequently evident, producing multiple hepatic abscesses that may dominate the gross appearance. Microscopically the ducts show extensive ductal and periductal fibrosis, a varying degree of acute and chronic inflammation, and proliferation of small mural glands (Figure 5-6). This appearance has been described as chronic proliferative cholangitis.^19,25 The small portal tracts display acute cholangitis and cholangitic abscesses together with portal edema, fibrosis, and inflammatory infiltration (Figure 5-7).

Biliary stones are another conspicuous finding. These are brown pigment stones: yellow-brown, friable, and earthy in appearance and composed principally of calcium bilirubinate. They vary in number and size and are generally associated with dense biliary sludge. The stones are thought to form primarily within the intrahepatic duct lumens, commonly in the larger bile ducts of the left hepatic lobe; the interlobular ducts are not involved.^25,31 Although often present in the extrahepatic ducts, these stones are infrequently found in the gallbladder -- in contrast with the usual Western-type gallstone disease.

In advanced cases, these pathologic processes combine to produce extensive fibrosis and atrophy of the parenchyma, often disproportionately affecting the left lobe. The end result is an irregular, coarsely scarred liver, distorted both by abscesses of differing ages and by cystically distended bile ducts filled with stones. Biliary cirrhosis is an uncommon complication.^7,37

The pathologic features are not specific, as they basically denote severe and progressive acute cholangitis and may be seen with bacterial cholangitis of any cause. Even intrahepatic biliary stones are not diagnostic; they may be seen, for example, with hepatic duct strictures in primary sclerosing cholangitis. One particular confounding condition is congenital dilitation of intrahepatic ducts (Caroli's disease). These cystic ducts are prone to recurring bouts of bacterial cholangitis and pigment stone formation. However, congenital hepatic fibrosis is often found as the background histology, and the dilated ducts are typically distributed diffusely through the liver (rather than predominantly in the left hepatic lobe), but there are exceptions.⁴

A noteworthy aspect of recurrent pyogenic cholangitis is its association with cholangiocarcinoma, which is noted in 2% to 5% of surgically treated cases.^6,13,18 This occurrence is not usually suspected preoperatively, and careful pathologic study of resected specimens is necessary. The carcinomas appear to arise from stone-bearing ducts within the liver; the adjacent ductal epithelium commonly shows atypical histologic features -- cellular crowding, stratification, and nuclear pleomorphism and hyperchromasia -- suggested as a precursor lesion.¹⁸

Acute cholangitis is identified in occasional cases of drug-induced cholestasis, although some reports of this association have not clearly discriminated between acute cholangitis and the neutrophil infiltration attending ductular proliferation. Those agents particularly implicated include allopurinol, carbamazepine, chlorpromazine, hydralazine, and sulindac.^15-17,35,38 The histologic background entails active cholestasis, a mixed portal inflammatory infiltrate (often with prominent eosinophils), proliferated ductules, and, in some cases, granulomas.

Additional instances of acute cholangitis are recorded in severe toxic shock syndrome and other septic conditions, fatal exertional heatstroke, occasional examples of acute allograft rejection, and various parasitic infestations, including ascariasis, fascioliasis, and echinococcosis with cyst rupture.^1,12,26,29

Primary biliary cirrhosis is a well-defined chronic cholestatic disease characterized by the destruction and loss of intrahepatic bile ducts.^1,69,101 As the paramount example of a disappearing bile duct disease, it has garnered great interest and attention. The term primary biliary cirrhosis is, strictly speaking, inappropriate as it refers only the end-stage cirrhotic outcome, but more accurate alternatives such as chronic nonsuppurative destructive cholangitis have not gained popularity.

Abundant circumstantial evidence suggests that primary biliary cirrhosis is an autoimmune disease, although the etiology is unknown and the pathogenetic mechanisms are undefined.^61,72 The destruction of biliary epithelium is generally considered to result from a lymphocyte-mediated attack akin to that seen in graft-versus-host disease or allograft rejection. This hypothesis is not established, but it gains support from ultrastructural studies showing activated lymphocytes with abundant pseudopods closely apposed to damaged epithelial cells.^44,84 These lymphocytes are primarily cytotoxic T cells (CD8+) with CD4+ helper-inducer T cells prominent in the surrounding infiltrate.^103,111 In addition, the biliary epithelial cells in primary biliary cirrhosis aberrantly express class II major histocompatibility molecules; this may enable the epithelial cells themselves to present autoantigens to T cells and thereby evoke or potentiate an autoimmune attack.^41,104 Such aberrrant expression, however, has also been noted with other types of cholangitis, so that it may be a secondary event.^107,126

The most distinctive immunologic abnormality in primary biliary cirrhosis is the presence of antimitochondrial antibodies. These autoantibodies react against a number of different mitochondrial antigens; the M-2 antigen characteristic of primary biliary cirrhosis has recently been identified as a component of the 2-oxo-acid dehydrogenase enzyme complex that resides along the inner mitochondrial membrane.^43,60 Although the significance of antimitochondrial antibodies remains enigmatic, their tight and specific alliance with primary biliary cirrhosis suggests that they reflect some important aspect of the pathogenesis rather than representing a minor secondary feature.⁵³ Nevertheless, exactly how the two disparate phenomena -- lymphocyte-mediated injury of bile ducts and autoantibodies to mitochondrial enzymes -- are connected remains the crucial but unanswered question. A diversity of other abnormalities in both humoral and cellular immune function have also been identified, but whether they are fundamental features or merely epiphenomena remains similarly unclear.

Clinical Features^{46,62,63,102,109}

Primary biliary cirrhosis is distinctively a disease of middle aged women: more than 90% of patients are female, most between 40 and 60 years but with a reported range from 24 to 78 years. Although men are infrequently affected, the disease is fundamentally similar in both sexes.^68,95 The epidemiology has been best studied in northern European populations, where the prevalence is estimated at 92 to 183 per million. Most cases appear sporadic, but examples of familial occurrence are recorded and a strong association with HLA-DR8 has been noted.^54,59

Common presenting symptoms are pruritus and fatigue; jaundice typically develops later but may sometimes represent an initial complaint. Other patients present with advanced disease as indicated by variceal bleeding, ascites, or encephalopathy. With greater frequency, however, the diagnosis is being established in patients who lack symptoms of liver disease. This asymptomatic group, which accounts for some 10% to 50% (or more) of cases in recent series, is usually detected because of abnormalities in laboratory tests performed during routine screening or evaluation of another illness.^45,58,67,94 Liver biopsy specimens may surprisingly show late-stage histologic features with fibrosis or even cirrhosis. Most asymptomatic patients eventually develop symptoms, sometimes only after many years, suggesting that their disease has simply been discovered early in its course, but other patients remain symptom-free for many years and may comprise a subgroup with a particularly indolent natural history.^40,77,88

Standard liver function tests in primary biliary cirrhosis reveal a cholestatic pattern. The serum alkaline phosphatase is almost always elevated, even early in the disease, although rare patients have normal levels.⁷⁶ Serum bilirubin values are often normal or near normal early in the course of disease, but rise as the disease progresses and have therefore been proffered as a prognostic indicator.¹⁰⁰ Circulating autoantibodies of a variety of types may be present, including rheumatoid factor and anti-smooth muscle, antinuclear, and antithyroid antibodies, but the most characteristic laboratory finding is the presence of antimitochondrial antibodies. These are present -- often at high titer -- in more than 90% of cases of primary biliary cirrhosis; in contrast, they are found in fewer than 10% of patients with other liver disease and are usually at a low titer.⁶³ The recent identification and cloning of the mitochondrial antigens reacting with these antibodies allows more sensitive and specific assays to be developed.^57,106

Primary biliary cirrhosis is often associated with other autoimmune diseases. The frequency of such associations depends on how extensively patients are evaluated and the diagnostic criteria used; in one study, 84% of patients had at least one coexisting autoimmune disorder and 41% had two or more.⁴⁸ These disorders include keratoconjunctivitis sicca, Sjögren's syndrome, scleroderma (often as the CRST variant -- calcinosis cutis, Raynaud's phenomenon, sclerodactyly, and telangiectasia), autoimmune thyroiditis, and polyarthritis and arthropathy. In many instances these are discovered only with specific testing, as they are often mild or subclinical conditions. The high prevalence of associated sicca syndrome has led to the concept of primary biliary cirrhosis as a general syndrome of ductal epithelial damage involving lacrimal and salivary glands and pancreas as well as bile ducts.⁵¹

As the disease progresses, the complications of prolonged cholestasis and cirrhosis increasingly dominate the clinical picture, and death ultimately results from hepatic failure, variceal hemorrhage, or sepsis.⁶² Mean survival times are reported to be between six and 12 years with a median five-year survival of about 65%.^{47,63,64,77,94} These overall figures conceal a marked variability in the rate of progression: from the time of diagnosis, some patients suffer rapid decompensation whereas others have a more protracted course. In particular, asymptomatic patients tend to have a more favorable prognosis, at least in the short term, but once symptoms appear, their survival significantly declines.^40,77,88 Unfortunately there is no completely effective therapy for primary biliary cirrhosis.^63,108 Ursodeoxycholic acid (ursodiol) has recently been shown to provide symptomatic benefit, although its effect on long-term prognosis is unclear.⁹³ Liver transplantation remains the only therapeutic option for end-stage disease; prognostic models have demonstrated that survival of transplanted patients is improved over that anticipated without transplantation.^74,86

Pathologic Features^{39,73,92,97,99}

The basis of primary biliary cirrhosis is the inflammatory destruction of interlobular and septal bile ducts. The resulting loss of ducts leads to a number of secondary changes along the periportal zone; these then progress to fibrosis and eventually cirrhosis ensues . Bile ducts are damaged in a patchy segmental fashion, and the distribution and rate of duct disappearance vary considerably. The disease therefore evolves unevenly across the liver, and the morphologic appearances accordingly differ, not only among patients, but also within a individual specimen. This complicates biopsy interpretation: the most dramatic histologic features may not be sampled, and thus the diagnosis must be confirmed or suggested on lesser pathologic grounds.

The histologic evolution of primary biliary cirrhosis has been commonly divided into four sequential stages. Most frequently used are the classifications proposed by either Scheuer or Ludwig and coworkers, as summarized in Table 5-2.^71,98 Scheuer's classification is primarily descriptive in nature, focusing on particular noteworthy lesions at each stage, whereas the scheme of Ludwig is a more general staging system based on the overall distribution and extent of abnormalities. Although these two classifications define and designate the stages somewhat differently, they are nonetheless broadly similar in practical application.

The value of staging has been challenged, however. The primary objection is that the nonuniform progression of primary biliary cirrhosis renders an assessment of stage unreliable and meaningless.^73,89,91 Certainly assigning a precise stage to a single specimen may be difficult or misleading, but with careful inspection, a rough appraisal can nevertheless usually be made. This appraisal, albeit imperfect and subject to sampling error, can be performed with reasonable observer variation and an accuracy sufficient to indicate prognosis.^46,50,64,71 In addition to furnishing an expedient means of summarizing the histologic extent of disease, staging serves a pragmatic function in organizing the wide range of morphologic abnormalities and directing attention to appropriate differential considerations.

The initial lesion -- and histologic hallmark -- is a distinctive pattern of bile duct injury often referred to as the florid duct lesion, but better described as chronic nonsuppurative destructive cholangitis.^97,98 This feature most conspicuously involves the medium-sized and larger interlobular ducts. The epithelium of the affected ducts is irregular and often hyperplastic with crowded, stratified nuclei (Figure 5-8). The epithelial cells are enlarged, commonly with eosinophilic and granular cytoplasm, but they may also show cytoplasmic vacuolation, particularly when intraepithelial invasion by lymphocytes is prominent. With more intense injury, the epithelium can become focally necrotic or ulcerated and the underlying basement membrane fragmented and destroyed, leaving remnants of PAS-positive material behind (Figure 5-9). These changes are distributed focally and variably along the length of the duct.

The smaller bile ducts are also affected, but in a less striking and less diagnostic fashion. They may exhibit irregular nuclei, variable cytoplasmic vacuolation, and occasional intraepithelial inflammatory infiltration (Figure 5-10).

The affected bile ducts are enveloped by a dense mononuclear inflammatory infiltrate that expands the portal tract and often invades the ductal epithelium. This infiltrate includes lymphocytes (sometimes with germinal centers), plasma cells, and macrophages in variable numbers. The macrophages may be scattered throughout the infiltrate or grouped into loose ill-defined aggregates or, less commonly, organized into well-developed sarcoidal granulomas (Figure 5-11).^66,82 A scattering of eosinophils is frequent, but neutrophils are generally uncommon. Bile duct lesions and granulomas become increasingly uncommon as the disease develops, although given the uneven rate of progression, they can sometimes be found even at the cirrhotic stage.

The eventual outcome of the destructive cholangitis is the disappearance of bile ducts. The ducts that vanish are principally are those with diameters less than 70 to 80 µm; the smallest ducts (under 35µm) especially suffer.⁸⁰ The departed ducts may disappear without leaving any evidence, but often their sites are marked by focal lymphoid aggregates or masses of PAS-positive material (Figure 5-12). Loss of bile ducts is an important histologic pattern, helpful in suggesting the diagnosis when the more obvious duct lesions are not present, yet it can be a subtle finding, requiring a focused search for hepatic arteries and portal tracts that lack associated bile ducts.^1,39,80

Although these bile duct alterations are the central histologic features, they may not be evident in some biopsy specimens, and a dense portal infiltrate of lymphocytes and plasma cells may be the only abnormality. The diagnostic possibilities are then considerable, although deeper sectioning of the specimen is sometimes useful in revealing the more specific findings. Additional problems for the pathologist arise from the assortment of nonspecific, and sometimes misleading, changes that are also frequently present. For example, the sinusoids often contain a reactive inflammatory infiltrate comprising lymphocytes, macrophages, and hypertrophic Kupffer cells (Figure 5-13).⁹² If sufficiently pronounced, this infiltrate may suggest an acute hepatitis, but it is distinguished by its focal distribution and lack of associated hepatocyte damage. Epithelioid granulomas -- typically found in the portal tracts -- can also appear within the lobules and may rarely be found in local lymph nodes or other organs.⁵²

Occasionally the lobules exhibit focal hepatocyte hyperplasia as manifest by thickened liver cells plates with a twin-cell arrangement; in extreme cases, this may yield parenchymal nodules and create an appearance resembling nodular regenerative hyperplasia.^81,92 In other cases, portal vein branches display irregular luminal narrowing with mural sclerosis.⁸³ Either of these lesions may explain the occasional instances of portal hypertension arising in the absence of cirrhosis. Finally, active cholestasis and canalicular bile plugs are sometimes noted in early disease, but are more commonly a feature of terminal decompensation.⁷⁸

With continued bile duct destruction, a periportal reaction develops that forms the basis for further disease progression.⁷⁹ This reaction entails several histologic patterns -- chronic cholestasis, periportal inflammation and necrosis, ductular proliferation, and fibrosis -- combined in a variable and overlapping manner. Various patterns may dominant within or among different biopsies, adding to the morphologic heterogeneity of primary biliary cirrhosis.

Chronic cholestasis, as defined in Chapter 4, is generally the predominant pattern. It is characterized by swollen and rarefied periportal hepatocytes, sometimes mildly bile-stained, that accumulate copper and copper-associated protein and occasionally show Mallory bodies (Figure 5-14). Attendant inflammatory cells, loose fibrous tissue, and proliferated bile ductules irregularly penetrate between and separate the affected liver cells. These inflammatory cells include a mixture of macrophages (frequently with a foamy appearance), sporadic lymphocytes, and a variable number of neutrophils (Figure 5-15).

Alternately, the lymphocytes and admixed plasma cells of the portal infiltrate can extend into the periportal zone to encroach on the parenchyma (Figure 5-16). This lymphocytic intrusion is accompanied by injury and destruction of the contiguous hepatocytes, generating a pattern of periportal inflammation and necrosis that is commonly known as piecemeal necrosis.^42,91,92 This pattern may be indistinguishable from the piecemeal necrosis seen in chronic active hepatitis and may therefore cause problems in differential diagnosis. Coinciding with the piecemeal necrosis, a focal lobular hepatitis may also be noted.⁹²

Bile ductular proliferation is a regular but nonspecific feature of the periportal reaction. These ductules commonly have flattened epithelial cells, lack lumens, and appear as thin, elongated structures that irregularly extend into the lobules (Figure 5-17). Often a mark of chronic cholestasis, these structures have been referred to as "atypical" ductules because of their aberrant shape and location; they may originate from periportal hepatocytes that have undergone ductular transformation.^97,112 Other ductules have a more conventional appearance with tubular profiles, cuboidal epithelium, and small, distinct lumens. All of these forms of periportal injury are attended by fibroblastic proliferation, and, as the disease progresses, fibrosis increasingly dominates the morphologic appearances. Initially the portal tracts are enlarged by portal and periportal fibrosis, but blunt fibrous septa develop with increasing stage. The septa radiate irregularly into the lobules and subsequently connect portal tracts to produce a pattern of biliary fibrosis (Figure 5-18). Additionally, in some cases fibrous septa appear to derive from bridging hepatic necrosis, just as in chronic active hepatitis, and a biliary pattern is not readily apparent.^71,99 Large hypocellular scars with thick-walled arteries may be seen in later stages (Figure 5-19).⁹² As the hepatic architecture becomes progressively distorted, parenchymal nodules form and ultimately cirrhosis develops. Bile ducts are typically few or absent and chronic cholestasis is often marked; the appearance is not specific, although active bile duct damage, granulomas, or residual lymphoid aggregates may remain as diagnostic clues.

Primary biliary cirrhosis, like other forms of cirrhosis, may be associated with hepatocellular carcinoma, although this is an unusual complication.^75,85

A variety of clinical, laboratory and histologic features have been found to correlate with survival and predict prognosis in primary biliary cirrhosis, although without complete agreement among the various studies.^47,50,55,94 The strongest prognostic indicator among the histologic features is the degree of fibrosis. This can be expressed by the histologic stage (Table 5-2) or graded on a scale of 0 to 3, but it is conveniently evaluated -- as with other progressive chronic liver diseases -- by assessing the low-power architectural pattern: simple portal and periportal fibrosis, bridging fibrosis, or cirrhosis. Regardless of the measure used and despite the constant problem of sampling error, more advanced fibrosis and, in particular, cirrhosis are independently associated with shortened survival.^47,55,94

Another marker of poor prognosis is active cholestasis with canalicular bile plugs; this, together with the corresponding serum bilirubin elevation, typically occurs with hepatic decompensation in advanced disease.¹⁰⁰ In addition, the presence of granulomas has been associated with a more favorable outcome in some studies yet not others, and is therefore a weak prognostic factor at best.^47,66,94

Almost any of the conditions characterized by duct injury or loss (Table 5-1) may potentially simulate primary biliary cirrhosis. Although the fully-developed florid duct lesions with granulomatous inflammation are characteristic, they are unfortunately found in only a minority of biopsy specimens.⁷⁰ In most cases the diagnosis may be suspected or confirmed by noting bile duct loss, chronic cholestasis, granulomas, or biliary fibrosis in the appropriate clinical and laboratory setting; a definitive diagnosis can then generally be established.

The foremost differential considerations include primary sclerosing cholangitis and chronic active hepatitis. Primary sclerosing cholangitis shares the same general pathologic sequence as primary biliary cirrhosis -- damage and loss of bile ducts with subsequent chronic cholestasis, increasing fibrosis, and cirrhosis -- so that histologic overlap is not surprising.¹⁰⁹ The distinction is aided by finding the obliterative periductal fibrosis characteristic of primary sclerosing cholangitis, but, just like the florid duct lesion, this is an infrequent biopsy feature.⁷⁰ However, cholangiography definitively settles the issue in most instances. Rare patients have been described with both diseases, although this appears to be no more than a chance occurrence.⁹⁶

Chronic active hepatitis may also be a stubborn differential problem.¹¹⁰ The difficulty arises principally because of the mutual features of periportal inflammation and piecemeal necrosis, but also contributing is the occasional finding of bile duct injury in chronic active hepatitis. This injury, which is particularly noted in hepatitis C infections, differs subtly from the bile duct lesions of primary biliary cirrhosis, but the the distinction is often difficult.^1,208 More importantly, bile ducts do not disappear in chronic active hepatitis, and chronic cholestasis and granulomas are generally absent. Stains for copper and copper-associated protein, by confirming the presence of chronic cholestasis, may therefore be useful; strong positivity (particularly in the absence of cirrhosis) favors primary biliary cirrhosis.^56,105 Most cases can be solved after all the clinical, serologic, and histologic data have been considered, but nevertheless some remain indeterminate. The possibility of a true hybrid syndrome with features of both disease has been suggested on the basis of overlapping features and differences in antimitochondrial antibody specificities, but this has not received wide approbation.^43,65

Other differential possibilities (discussed below) include prolonged drug-induced cholestasis by such agents as chlorpromazine and tolbutamide and the rare examples of sarcoidosis that demonstrate granulomatous destruction of bile ducts. Furthermore, bile duct damage and destruction resembling that in primary biliary cirrhosis are essential features of both hepatic allograft rejection and hepatic graft-versus-host disease, as reviewed in Chapter 14. Indeed, this similarity has generated considerable controversy about whether primary biliary cirrhosis can recur in transplanted livers or whether the changes only represent chronic allograft rejection.^49,87,90

Primary sclerosing cholangitis is an idiopathic condition characterized by obliterative fibrosis of the bile ducts. This produces irregular stricturing and ectasia that involves the entire biliary tract, in any combination or degree, from the interlobular ducts to the common bile duct. Typically both the extrahepatic and intrahepatic ducts are affected, although in some instances, alterations are confined to one or the other site. Since the major bile ducts are consistently involved, the definitive diagnostic procedure is cholangiography. The small intrahepatic bile ducts seen in liver biopsy specimens are also frequently affected, but only rarely without concomitant large duct disease. Cholangiography and liver biopsy therefore provide complementary information: the status of the large bile ducts is indicated by the radiographic appearances and the state of the small bile ducts and liver parenchyma by the histologic appearances. The general result of these biliary processes is chronic cholestasis, periportal inflammation, progressive fibrosis, and, finally, biliary cirrhosis.

Primary sclerosing cholangitis had been considered a rare disease, but the frequency of the diagnosis has markedly increased since the mid-1970's. This increase originates from the wider availability and use of cholangiography and a greater awareness of the disease, prompted in part by better appreciation of its association with chronic ulcerative colitis. The heightened recognition of this disorder has correspondingly expanded its clinical and pathologic spectrum, and patients with asymptomatic or early disease constitute a rising proportion of reported cases.^137,183

The etiology and pathogenesis of primary sclerosing cholangitis are obscure and its connection with ulcerative colitis unexplained. A genetic predisposition is suggested by the occasional occurrence of familial cases and by the association with histocompatibility haplotypes HLA-B8, DR3, and DR2.^166,168 Additional observations point to the pathogenetic importance of immunologic mechanisms.^123,148 An assortment of abnormalities in humoral and cellular immune function have been identified, including, for example, circulating immune complexes, autoantibodies to neutrophil cytoplasmic components and colonic antigens, inhibited leucocyte migration in response to biliary antigens, and altered lymphocyte subsets in the peripheral blood, including an increase in autoreactive suppressor/cytotoxic T-lymphocytes.^123,131,147 In addition, the biliary epithelial cells in early disease have been shown to aberrantly express class II major histocompatibility determinants, which may then induce or facilitate an autoimmune T-cell response.^120,126 Unfortunately many of these findings, although compatible with an immunologic process, are not specific for primary sclerosing cholangitis and may simply represent secondary phenomena. While an immune-mediated pathogenesis is an attractive possibility, it is yet unproved. Other pathogenetic hypotheses have postulated such factors as infections, toxins, or damage to the peribiliary arteriolar plexus, but their roles are largely speculative.^145,148,153

Clinical Features^{124,143,145,146,153,172}

Primary sclerosing cholangitis is primarily a disease of young adult men. Approximately 60 to 70% of the patients are male, usually between the ages of 25 and 45 years, although the age range spans from 2 to 80 years.^{128,132,133,175} Cases have also been reported in infants, but whether this represents an entity distinct from biliary atresia is unclear.¹¹⁴

The clinical presentation varies. Patients commonly complain of fatigue, pruritus, and jaundice, often with an insidious onset. Some patients manifest recurring attacks of bacterial cholangitis with abdominal pain, fever, chills, and jaundice; often they have previously undergone biliary reconstructive surgery.¹⁴³ With advanced disease, ascites, variceal bleeding, or encephalopathy may be present. Increasingly, however, the disease is recognized in asymptomatic patients. These patients constitute 10% to 30% of cases in recent series and are generally discovered because of unexplained abnormalities in liver tests, often in association with ulcerative colitis.^137,141,165 Most asymptomatic patients eventually develop evidence of progressive disease, but some suffer a relatively indolent course and may remain symptom-free for prolonged periods.^{113,137,144,165}

Laboratory findings reflect the cholestatic nature of the disease. The serum alkaline phosphatase is almost invariably elevated, although its level fluctuates and can be normal in some instances.^115,133 Moderate increases in serum transaminase values are common, and elevated serum bilirubin, albumin, or prothrombin times are variably seen. Autoantibodies are not generally found, in contrast to primary biliary cirrhosis, but hypergammaglobulinemia is noted in about one-third of patients.

A most intriguing aspect of this disorder is its relationship with chronic inflammatory bowel disease. Approximately 70% to 75% of cases of primary sclerosing cholangitis are accompanied by inflammatory bowel disease: primarily this is ulcerative colitis, although Crohn's disease, often with extensive colonic involvement, is found in up to 10% of patients in recent series.¹³⁴ Conversely, some 2% to 7% of patients with ulcerative colitis have concomitant primary sclerosing cholangitis, which is therefore the most common form of associated chronic liver disease.^163,173 Since either disorder may be asymptomatic, these figures may underestimate the true frequencies; specific, directed searches have yet to be performed in unselected patients. Despite their association, these two conditions have independent natural histories. The characteristics and course of primary sclerosing cholangitis, for example, are not substantively different whether inflammatory bowel disease is present or not; the minor discrepancies that have been noted likely reflect variations in the stage of the disease at presentation.^143,169 Although the diagnosis of colitis typically antedates the recognition of primary sclerosing cholangitis, the reverse also occurs, and, furthermore, the severity, duration, or extent of colitis does not directly correlate with the occurrence or outcome of the liver disease.^113,125 Indeed, even proctocolectomy does not prevent primary sclerosing cholangitis and has no distinct influence on its natural history.¹²² Their independence implies that, rather than being causally related, these two conditions share major etiologic or pathogenetic factors. Primary sclerosing cholangitis has also been rarely associated with other diseases, among them inflammatory fibrosing lesions of the retroperitoneum, mediastinum, orbit, thyroid and neck (Riedel's struma), and penis (Peyronie's disease).^145,146

No specific therapy for primary sclerosing cholangitis exists. A number of immunosuppressive and anti-inflammatory agents has been tested, and aggressive surgical procedures involving resection of the extrahepatic biliary tree and reconstruction with prosthetic transhepatic shunts have been described.^{139,146,148,158} Unfortunately, none of these approaches has been documented to change the natural history of the disease, and most treatment is therefore aimed at managing bouts of bacterial cholangitis and complications of prolonged cholestasis. Dominant strictures in major ducts can be dilated or decompressed by percutaneous or endoscopic techniques, producing short-term relief of biliary obstruction.^129,145 The ultimate therapy for end-stage disease is liver transplantation; the results are comparable to other adult liver diseases with survival rates up to 88% at four years.^142,148,157 Following transplantation, some patients have developed unexplained stricturing of the common or hepatic bile ducts, suggesting possible recurrent disease, although similar changes have also been seen after transplantation for other conditions.¹⁵³

The outcome of primary sclerosing cholangitis varies greatly, in part reflecting its widening clinical spectrum with increased recognition of early and asymptomatic cases.^133,164 In most patients, decompensated cirrhosis with worsening jaundice, portal hypertension, and liver failure eventually develops and leads to death. Overall the median survival ranges from 10 to 12 years with a five-year survival rate between 65% and 85%.^{113,133,137,144,182} Asymptomatic patients have a more prolonged course, but they suffer a significantly higher mortality than the general population with a five-year survival rate estimated at 88%.¹⁶⁵

A remarkable complication of primary sclerosing cholangitis is the occurrence of cholangiocarcinoma.¹⁷⁰ Often this is not suspected clinically and is only discovered when the liver is examined at autopsy or liver transplantation. The exact risk is unknown, but a crude prevalence rate is estimated at 6% to 9%.^{113,133,171,182} This association has been controversial, as the two have frequently been considered mutually exclusive diagnoses, but careful clinical and pathologic investigations indicate that bile duct carcinoma can develop in preexisting primary sclerosing cholangitis.^{136,159,170,181}

The diagnosis of primary sclerosing cholangitis is basically a cholangiographic one. The characteristic features comprise widespread, multifocal strictures and irregular narrowing of the ducts, giving rise to a nodular, beaded appearance (Figure 5-20). Long segmental strictures may also form, and the intrahepatic ducts may show decreased branching, a look likened to a pruned tree.^145,154,155 In over 85% of cases both the extrahepatic and large intrahepatic bile ducts are involved, with the most severe involvement often centered at the bifurcation of the hepatic ducts, but occasionally only one site -- usually the intrahepatic ducts -- are affected.^{121,125,133,137,182} In addition, abnormalities in the gallbladder and pancreatic ducts are described.^138,140 Although the cholangiographic changes are distinctive, other conditions, particularly bile duct carcinoma, can produce a similar appearance and must be considered in the radiographic differential diagnosis.

The liver in primary sclerosing cholangitis displays a wide spectrum of abnormalities that encompasses changes attributable to the primary disease process in addition to those abnormalities that are merely consequent to large-duct biliary obstruction.¹ The histologic findings are remarkably heterogeneous, and many are not diagnostic of the disease. Indeed, in some instances, liver biopsies appear normal or show only minor reactive changes. In these cases, the histology can be considered only compatible with the diagnosis, and the definitive diagnosis depends on radiographic findings. In general, the overall process begins with reactions that are centered on the portal and periportal regions; these progress with increasing fibrosis to biliary cirrhosis .

The histologic features have frequently been described with the four-tiered staging scheme of Ludwig and coworkers (Table 5-3).¹⁵² Similar to their staging proposal for primary biliary cirrhosis, this scheme emphasizes architectural alterations rather than any specific morphologic features. Because of the heterogeneity and irregularity of the morphologic features, however, the merit of histologic staging has been questioned.¹⁴⁵ While there are practical limitations in assigning a precise stage to a variegated process, staging nevertheless serves as an important prognostic indicator. It is also useful in understanding the progression and pathologic extent of the disease.^133,182 The pathologist should therefore make a best estimate of the histologic stage, despite its shortcomings.

The classic lesion of primary sclerosing cholangitis is concentric periductal fibrosis associated with injury and atrophy of the ductal epithelium.^70,116 The involved duct is encased by a layered sheath of fibrosis -- commonly known as "onion-skin" fibrosis -- that progressively narrows and obliterates its lumen (Figure 5-21). The basement membrane, although intact, becomes thickened and reduplicated.¹⁶² Epithelial cells display various degrees of damage and destruction, and attendant inflammation is typically scant. The affected ducts eventually vanish; many depart without any histologic trace or with only a loose lymphoid aggregate, but others are replaced by nodular fibrous scars, a lesion referred to as intrahepatic obliterative cholangitis (Figure 5-22).^117,156 Although characteristic of primary sclerosing cholangitis, obliterative periductal fibrosis is unfortunately found in only a minority of biopsy specimens.^70,116,125 Periductal fibrosis alone is more commonly noted, but it is also found in other conditions, including chronic biliary obstruction, and occasionally as an incidental abnormality without any clear explanation. However, the combination of periductal fibrosis with ductal atrophy and lumen obliteration, however, strongly suggests primary sclerosing cholangitis.

More prevalent, but less diagnostic, are a variety of other bile duct alterations.^{116,125,135,153} Some small ducts demonstrate epithelial damage unaccompanied by periductal fibrosis (Figure 5-23). The epithelium may be irregular, often flattened or vacuolated, and focally infiltrated by mononuclear inflammatory cells; the nuclei are enlarged and reactive appearing, and a thin rim of hyalin fibrosis may encircle the duct. A more distinctive feature, however, is a reduction in bile duct numbers. This loss of ducts is characterized by finding hepatic arteries and portal tracts without their attendant ducts (Figure 5-24). This is noted in about 60% of cases, depending on the stage of the disease, but may be focally distributed and difficult to discern. A careful and specific inspection of the biopsy is therefore required, but worth the effort since the observation greatly narrows the diagnostic possibilities.

Other portal tracts show background changes of biliary obstruction, including bile ductular proliferation, an inflammatory infiltrate that includes neutrophils, and portal edema and fibrosis (Figure 5-25). These obstructive features presumably reflect the large duct occlusion evolving downstream, and, by themselves, are not specific. Within a single biopsy specimens, however, portal tracts with ductular proliferation often coexist with portal tracts that lack bile ducts. This seemingly incongruous combination is perhaps the most common histologic pattern in primary sclerosing cholangitis.^116,150

The portal tracts also generally contain an inflammatory population, usually of mild degree, that includes primarily lymphocytes (sometimes with lymphoid follicles) and plasma cells, with occasional neutrophils and eosinophils. When mild or the sole finding, this appearance may suggest chronic persistent hepatitis or nonspecific portal inflammation. Neutrophils may be especially conspicuous when bacterial cholangitis supervenes, and granulomas are notably rare. In some cases, the mononuclear infiltrate and spreads outside the portal tract into the periportal hepatocytes (Figure 5-26); this periportal inflammation and piecemeal necrosis can mimic chronic active hepatitis.^125,174

The lobules are largely uninvolved. Canalicular cholestasis may occasionally be present and, if a dominant biliary stricture or a complicating cholangiocarcinoma have developed, may be marked. Fatty change may be present.

With advancing disease, the periportal region becomes affected, with chronic cholestasis prominently adding to the overall appearance. The periportal hepatocytes become swollen and lucent; they gain copper and copper-associated protein and are occasionally adorned by Mallory bodies (Figure 5-27). Increased stainable copper is found in a majority of cases, although it may be missing in early examples, and copper stains are therefore a useful -- but not specific -- diagnostic adjunct.^125,133,151 In addition, chronic cholestasis is variably associated with a mixed population of periportal inflammatory cells and bile ductular proliferation, although the degree of inflammation is generally mild.

These various periportal reactions are attended by increasing periportal fibrosis; small fingers of connective tissue extend among the periportal hepatocytes, forming the basis of disease progression. The portal tracts are enlarged and expanded by fibrosis, but are usually poor in inflammation. Portal-portal fibrous septa begin to evolve, producing a pattern of biliary fibrosis similar to that seen, for example, in primary biliary cirrhosis (Figure 5-28). The cirrhotic stage is characterized by the jigsaw-puzzle nodules typical of biliary cirrhosis. The bile ducts are substantially missing, and changes of chronic cholestasis persist and worsen. Inflammation is often minimal, however, and canalicular cholestasis may appear as evidence of decompensation.

The extrahepatic and large intrahepatic bile ducts show nonspecific and nondiagnostic fibrous thickening of the duct wall together with a variable inflammatory component (Figure 5-29). The larger intrahepatic ducts may become greatly dilated, forming cholangiectases filled with biliary sludge; this change is very suggestive of primary sclerosing cholangitis, although the possibility of Caroli's disease should be entertained.^135,154 Biopsies from the extrahepatic bile ducts may be obtained to exclude a cholangiocarcinoma. This can be a extraordinarily difficult problem: the normal periluminal glands entrapped within the mural fibrosis can display reactive changes that strongly resemble carcinoma. Pronounced cytologic atypia, intraglandular bridging, and perineural invasion are the best clues to a malignancy.^161,167

Several large studies have examined clinical, biochemical, and histologic features of primary sclerosing cholangitis in an effort to better define the prognosis.^{133,137,144,182} A number of such prognostic indicators have been identified, many of them differing among studies. The histologic stage, however, has been a consistent and independent prognostic factor on multivariate analysis. In particular, a poor prognosis is suggested by the presence of bridging septal fibrosis or cirrhosis, as with other progressive forms of chronic liver disease.

Primary sclerosing cholangitis can resemble a broad range of other hepatic conditions. The most diagnostic lesion is obliterative periductal fibrosis, but this is infrequently found. The diagnosis is more typically suggesting by finding bile duct loss, chronic cholestasis, obstructive-type portal alterations, or biliary fibrosis. These features should be carefully searched for in biopsies of any patient with inflammatory bowel disease, especially if cholestatic biochemical tests are present.¹⁷⁴ The diagnosis can then be corroborated by cholangiography, which is the definitive diagnostic tool.

Chronic active hepatitis is among the differential considerations because both conditions may display prominent periportal inflammation and piecemeal necrosis. In addition, bile duct damage can be a feature of chronic hepatitis, especially with hepatitis C (non-A, non-B hepatitis). The issue is further confounded because patients with ulcerative colitis, in addition to their propensity for primary sclerosing cholangitis, are also at increased risk of chronic active hepatitis, and the hepatitis C virus is often responsible.^127,130,180 Despite these similarities, chronic active hepatitis can generally be distinguished by the normal number of bile ducts, the frequent presence of prominent ductular proliferation, and the lack of chronic cholestasis. Copper stains are therefore useful; most examples of primary sclerosing cholangitis will be positive, whereas, in the absence of cirrhosis, chronic active hepatitis is generally negative.^56,105,180

The histologic overlap between primary sclerosing cholangitis and primary biliary cirrhosis is apparent: both are characterized by bile duct destruction and loss, and chronic cholestasis and biliary fibrosis are the common means of progression. As a rule, primary biliary cirrhosis tends to be more inflammatory (including granulomatous inflammation) and less fibrotic process than primary sclerosing cholangitis. This is reflected in the different nature of their distinctive forms of bile duct injury -- the florid duct lesion in primary biliary cirrhosis and obliterative periductal fibrosis in primary sclerosing cholangitis. Nevertheless, the distinction may be impossible on histologic grounds, and the diagnosis must rest on clinical, serologic, and radiographic criteria.¹⁰⁹

Both chronic biliary obstruction and primary sclerosing cholangitis can produce an identical histologic picture with periductal fibrosis, bile ductular proliferation, and portal inflammation. This is not surprising because primary sclerosing cholangitis basically represents a variant of prolonged large-duct occlusion, and many of the morphologic lesions may well derive from that source. In the usual case of chronic obstruction, however, the portal tracts are uniformly involved, bile duct loss is not seen, and the periductal fibrosis lacks the obliterative quality and associated atrophy seen with primary sclerosing cholangitis.¹¹⁶ These ductal changes have been reported, however, in exceptional cases of chronic large-duct obstruction.⁷⁰

Likewise, other conditions associated with bile duct damage or loss (Table 5-1) may mimic primary sclerosing cholangitis, and the clinical circumstances and radiographic details are then essential to the diagnosis.

Pericholangitis

This term is often employed to describe the inflammatory lesions of the portal tracts that are found in patients with inflammatory bowel disease, usually ulcerative colitis.^149,150,179 This concept of pericholangitis, however, has a long and controversial history. Part of the problem is that many reports predate the diagnostic techniques and criteria used currently, and the implications of the results are accordingly difficult to discern today.

By whatever name, portal inflammatory lesions are common in inflammatory bowel disease: found in 10% to 20% of unselected patients, they are noted in as many as 80% of patients with clinical or laboratory abnormalities suggesting liver disease.^{119,127,130,179} Pericholangitis is therefore often said to be the most frequent hepatic abnormality seen in inflammatory bowel disease.

These portal abnormalities include a variety of histologic changes: portal tract inflammation with lymphocytes, plasma cells, and scattered neutrophils and eosinophils; bile duct injury and fibrosis; bile ductular proliferation; piecemeal necrosis; and periportal and bridging fibrosis.^160,179 Although pericholangitis connotes inflammation centered on the bile ducts, this is not generally described.

Pericholangitis is clearly not a specific entity, but, by modern criteria, a combination of several disorders. At cholangiographic examination, many patients diagnosed as having pericholangitis are found to have typical primary sclerosing cholangitis.^{118,151,174,177} Other patients manifest normal cholangiograms, but have cholestatic biochemical tests and histologic features compatible with primary sclerosing cholangitis; they appear to have primary sclerosing cholangitis that involves only the small intrahepatic ducts.^149,178,180 The natural history of this subgroup is not clearly defined; the sparse evidence suggests that some patients may progress to large duct involvement while others have an more indolent disease.^119,180

Consequentially, pericholangitis most often represents the intrahepatic component of the primary sclerosing cholangitis spectrum. Other reported cases of pericholangitis probably include instances of chronic persistent hepatitis or chronic active hepatitis, and some likely exemplify nonspecific reactive inflammation. Because of this ambiguity, the term pericholangitis is best eliminated from the pathologist's diagnostic or descriptive vocabulary. The practical message is that liver biopsies from patients with inflammatory bowel disease should be scrutinized for features suggestive of primary sclerosing cholangitis; if present, cholangiography should be recommended.

Primary sclerosing cholangitis is distinguished from other disorders associated with multifocal strictures and irregularity of the bile ducts. Although these conditions display cholangiographic abnormalities identical to primary sclerosing cholangitis, they are differentiated by their association with recognized biliary insults such as operative trauma, choledocholithiasis, infectious organisms, or toxic agents. These secondary forms of sclerosing cholangitis are therefore basically a differential diagnostic problem for the radiologist.

These disorders generally affect only the large bile ducts, sparing the small interlobular ducts from direct destruction, although rare exceptions have been reported. The underlying histologic picture is accordingly that of biliary obstruction; the lack of small duct involvement distinguishes them histologically from primary sclerosing cholangitis.

Immunodeficiency syndromes are among the considerations with the acquired immunodeficiency syndrome (AIDS) being the predominant cause.^{188,190,199,205} Similar changes have been reported, however, with various congential immune deficiencies.^{185,190,194,200,201} The suspicion is that opportunistic infections cause the duct damage, and, in particular, Cryptosporidia and cytomegalovirus have frequently been implicated.^{184,188,189,199} Other organisms, including fungi and parasites, may also infrequently infect the bile ducts and lead to fibrous scarring.

Sclerosing cholangitis has also been ascribed to chemical agents. Infusion of floxuridine into the hepatic artery to treat hepatic metastasis has yielded sclerosing cholangitis in an appreciable number of instances.^{191,195,196,198} This injury appears to be ischemic in origin, arising from damage to the peribiliary vascular plexus. Similar changes have developed from the use of formalin and other caustics in the treatment of hepatic eccinococcal cysts.^186,203

Langerhans cell granulomatosis (histiocytosis X) may involve the large bile ducts and produce sclerosing cholangitis-like cholangiographic abnormalities.^197,204 Similarly, uncommon instances of cystic fibrosis may also demonstrate sclerosing cholangitis, although simple strictures of the distal common duct are more common.^187,193,202

Bile duct injury is noted in occasional examples of acute or chronic hepatitis.^208,214,221 Hepatitis C (non-A, non-B hepatitis) is the most common offender, although other causes of hepatitis, including the Epstein-Barr virus and cytomegalovirus, have also been implicated. The epithelial cells are swollen and disrupted with irregular, stratified nuclei and frequent cytoplasmic vacuolation (Figure 5-30). A dense aggregate of mononuclear cells typically encircles the affected duct, and epithelial infiltration by lymphocytes is common. Some ducts are also accompanied by diverticular outpouchings, as demonstrated by three-dimensional reconstruction studies.²²⁴ The bile duct injury in hepatitis is reversible and does not result in duct destruction. Although the duct lesions resemble those of primary biliary cirrhosis, they are distinguished since bile duct numbers are not reduced and granulomas and chronic cholestasis are absent.

A variety of drugs and toxins can give rise to bile duct abnormalities, typically within a background that includes canalicular cholestasis and a variable degree of hepatocyte damage and lobular inflammation. These bile duct changes are often mild and inconsequential, consisting of only minor aberrations in the size and shape of epithelial nuclei. Also encountered, however, is more striking injury manifest by markedly irregular, and occasionally flattened, ductal epithelium, primarily of the smallest interlobular ducts. The epithelial cells acquire vacuolated, eosinophilic, or basophilic cytoplasm with enlarged regenerative nuclei; isolated cells cells may undergo necrosis. Accompanying these features is a mixed portal inflammatory infiltrate of variable degree with prominent eosinophilia in some instances. This type of injury has been noted with chlorpromazine, tolbutamide, phenytoin sodium, chlorpropamide, and ajamline.^1,210,223

Some drugs give rise to an acute cholangitis with ductal infiltration by neutrophils, as discussed above. In addition, occasional agents produce shrinkage and degeneration of the ductal epithelium unattended by much inflammation (Figure 5-31). The reported culprits include paraquat and contaminated rapeseed oil, the cause of the Spanish toxic oil syndrome.^218,222

In most drug-related bile duct injuries, once the offending drug is stopped, the affected ducts recover. In rare instances, however, progressive disappearance of bile ducts has been encountered; the implicated drugs include phenothiazines, imipramine, thiabendzole, ajmaline, chlorpropamide, and ampicillin, among others.^{207,209,212,215,217} In addition to duct loss, liver biopsies may show chronic cholestasis with periportal hepatocyte swelling and copper deposition, patchy ductular proliferation, and portal inflammation and fibrosis. Although these cases share clinical and histologic features similar to primary biliary cirrhosis, the rapid onset of jaundice and the absence of antimitochondrial antibodies permit the distinction. As with any drug-induced hepatic injury, the diagnosis primarily rests on the clinical history and the temporal relationship between drug usage and liver damage.

Singular patients with sarcoidosis develop progressive destruction of bile ducts by granulomas, leading to chronic cholestasis and eventually to biliary cirrhosis.^206,219,220 Obviously such cases may be difficult to distinguish from primary biliary cirrhosis, although antimitochondrial antibodies are not present. The issue is confounded, however, isolated case reports describing patients with both diseases.²¹³

Additional Causes

Damage to interlobular bile ducts -- with their disappearance in some cases -- is characteristic of hepatic allograft rejection and graft-versus-host disease (Chapter 14) as well as certain forms of infantile cholestasis such as biliary atresia and bile duct paucity (Chapter 6). Bile duct damage has also been rarely reported with sepsis, presumably due to the action of endotoxins.²²⁵ Finally, unusual patients have diminished bile ducts, but none of the above disorders; these cases have been referred to as idiopathic adulthood ductopenia.^211,216