Clinical Features and Epidemiology

The incidence of classic (type 1) AIH is 1.9 cases per 100,000 individuals per year, which is a higher rate than for PBC or PSC. Patients of any age may be affected. Concurrent autoimmune diseases of other types are common (34% of women and 17% of men), and 78% of AIH patients are women.⁷ A subtype of AIH, characterized by the presence of anti–liver-kidney microsomal antibody (anti-LKM), is sometimes referred to as AIH type 2.⁸ It is more common among children and females than males.⁸

Individuals with certain human leukocyte antigen (HLA) types are at increased risk for AIH, although testing for the various phenotypes is not necessary in routine clinical practice. The HLA-A1, HLA-B8, HLA-DR3, and HLA-DR4 phenotypes are associated with type 1 AIH.^1,8

In patients with AIH, serum biochemical values vary considerably, which is a reflection of the grade and stage of disease. During periods of inactive (quiescent) disease, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values may be normal. However, during disease flare-ups, the serum aminotransferase values may range from the low hundreds to an excess of 1000 IU/mL. Serum alkaline phosphatase values usually are normal or only minimally elevated. Bilirubin values are often normal but may be elevated during bouts of clinical activity. Hypergammaglobulinemia, which is usually evident even in early-stage disease, is a defining feature of AIH.¹ Cases of AIH that progress to cirrhosis have elevations of bilirubin levels and biochemical evidence of cirrhosis (e.g., thrombocytopenia, decreased serum albumin, prolonged prothrombin time).

Pathogenesis

Similar to other types of autoimmune diseases, AIH is caused by a defect in suppressor T cells that leads to disordered immunoregulation and production of a variety of autoantibodies, some of which probably act against hepatocyte surface antigens. The defect in suppressor T cells may occur de novo (most common) or after a triggering episode. Hepatitis A¹⁰ and a variety of drugs¹¹ are among the best described inciting factors. Although most of the autoantibodies in AIH patients are not specific for AIH and may not act directly in the pathogenesis of the disease, their identification is often helpful diagnostically.

Antinuclear antibodies (ANAs) are identified in approximately 80% of patients with AIH and typically occur in a titer greater than 1 : 40. Anti–smooth muscle antibody (ASMA) is positive in about 70% of AIH patients, also occurring in a titer greater than 1 : 40. The finding of high-titer ANA or ASMA, or both, in a patient with clinical suspicion of AIH defines the type 1 form of this disorder, which is the most common and represents the prototypical type. However, ANA and ASMA may be identified in the serum of patients without AIH and in patients with other types of liver diseases, such as hepatitis C, alcoholic liver disease, or nonalcoholic steatohepatitis, but in these cases, the titer is usually low.

The presence of anti-LKM is a characteristic feature of type 2 AIH, and it is usually detected in the absence of high-titer ANA or ASMA. High-titer anti-LKM in the absence of anti–hepatitis C virus antibody (anti-HCV) is designated type 2 AIH.¹² This uncommon form of AIH occurs most often in children. Low-titer anti-LKM with anti-HCV is designated type 2b AIH by some, although it probably does not reflect an important pathologic entity. This type of AIH is more appropriately viewed as a variant of hepatitis C, which also has autoimmune features. Antibodies against soluble liver antigen (SLA), liver-pancreas (LP) antigen, and asialoglycoprotein receptor (ASGPR) may also be identified in type 1 AIH, but they are less diagnostically useful.^13,14

Although the precise mechanism of immune attack on the liver remains unknown, based on the histopathology, it is postulated that hepatocytes, rather than biliary epithelial cells, are the primary target. Necrosis of hepatocytes is usually most prominent at the level of the limiting plate (i.e., zone 1, periportal hepatocytes). This process is also referred to as piecemeal necrosis, interface hepatitis,¹⁵ or troxis hepatitis.¹⁶ A predominant attack on hepatocytes in zone 3 (pericentral) occurs in some cases.¹⁷ Necrosis of random hepatocytes throughout the hepatic lobules is also common in AIH and is recognizable as acidophil bodies or their remnant, lipofuscin-laden macrophages.

Pathology

Gross examination of the liver in AIH contributes little diagnostically. In early-stage disease, the liver usually appears normal. If submassive or massive hepatocyte necrosis occurs during episodes of severe activity, the external surface of the liver may appear shriveled, and cross sections may show areas of confluent parenchymal collapse. While the disease progresses, cirrhosis eventually develops, and it is typically composed of tan to brown micronodules and macronodules (Fig. 47.1), similar to the pattern that occurs in chronic viral hepatitis. Occasionally, a greenish discoloration may be seen, similar to cirrhosis resulting from chronic biliary disorders.

Although the pathologic lesions in AIH vary considerably according to the grade and stage of disease (Table 47.3), chronic inflammation composed primarily of lymphocytes and a considerable number of plasma cells in portal tracts is a near-constant microscopic feature. However, during periods of quiescent disease (i.e., remission), portal inflammation may be the only histologic abnormality. In some cases, little or no inflammation is detected (Fig. 47.2). A small number of intraepithelial lymphocytes may be found within bile duct epithelium. However, bile duct destruction and loss are not features of AIH and should alert the pathologist to a possible diagnosis of PBC or an overlap syndrome.

During flares of disease activity, interface hepatitis, which is the pathologic hallmark lesion of active AIH, is typically prominent. This lesion is characteristic of AIH, but it is not specific. Interface hepatitis is also common in viral- and drug-associated forms of chronic hepatitis, in PBC, and in other diseases. Interface hepatitis in AIH is characterized by a prominent lymphohistiocytic infiltrate at the portal tract mesenchymal-parenchymal junction with accompanying histologic evidence of liver cell damage (Fig. 47.3, A). CD8-positive T cells are a dominant subset of lymphocytes within areas of interface hepatitis, and CD4-positive T cells predominate within the portal tracts.¹⁸

Damage caused by interface hepatitis may appear as overt necrosis of whole hepatocytes (i.e., acidophil bodies) or as slow destruction of hepatocytes caused by ingestion of small portions of cytoplasm by activated lymphocytes, described vividly by Wang and associates as troxis, which is the Greek word for “gnaw” or “chew.”¹⁶ In AIH, plasma cells are normally quite conspicuous, particularly compared with other disorders such as chronic viral hepatitis (see Fig. 47.3, B).

In addition to portal and periportal inflammation, lobular damage usually occurs in AIH. It manifests as some degree of anisonucleosis, ballooning degeneration, hepatocellular swelling, neocholangiole formation, cholestasis (rare), and acidophil bodies accompanied by a lymphocytic and plasmacytic infiltrate (Fig. 47.4). The degree of lobular damage contributes to the grade of disease. Although hepatocellular damage is usually panlobular, in some cases, zone 3 (centrilobular) damage may be prominent,¹⁶ resembling periportal interface hepatitis but occurring in the centrilobular zones of the liver (Fig. 47.5). This may represent an early form of AIH that precedes overt portal-dominant (classic) AIH.¹⁹

Lobular hepatitis is typically prominent during bouts of disease activity, but it may resolve spontaneously or as a result of immunosuppression. The activity grade can be assessed semiquantitatively, similar to hepatitis C. However, compared with chronic hepatitis C, AIH may have a much broader range of disease activity, from complete inactivity at one end of the spectrum to submassive or massive necrosis with confluent necrosis (see Fig. 47.4) at the other. Liver sampling is only rarely performed immediately after treatment, but rapid resolution of lobular necrosis with complete or incomplete resolution of portal inflammation and resolution of fibrosis is typical.

Cholestasis is usually not a feature of AIH, but a mild degree may be seen in more severe cases with marked lobular inflammation (Fig. 47.6). In contrast to hepatitis C, steatosis is not a typical feature of AIH. Lymphocytic venulitis involving portal or central veins may occur in high-grade disease, but it does not usually result in vein destruction or substantial endothelial damage, as in acute allograft rejection.

Similar to chronic viral hepatitis, progression of fibrosis (stage) from portal to initially periportal and then to bridging fibrosis and cirrhosis occurs in AIH. Even after cirrhosis has developed, interface hepatitis may persist within fibrous septa or regenerative nodules (i.e., active cirrhosis). Alternatively, the inflammation may subside completely, resulting in inactive cirrhosis.

Although AIH is a chronic disease, onset occurs at some point, and the disease may be regarded as acute. Relatively little is known regarding the pathology of acute-onset AIH. Lefkowitch and colleagues reported hepatocyte swelling, acidophil bodies, steatosis, cholestasis, piecemeal necrosis, and prominent portal plasma cells in initial liver biopsies from two patients with clinical features of AIH.²⁰ Another study that examined liver samples from patients with clinical disease of less than 6 months’ duration found that with the exception of one case of lobular hepatitis with confluent necrosis (i.e., submassive hepatic necrosis), 25 of 26 of patients already had histologic changes of chronicity, such as portal inflammation and fibrosis (7 of 26) or bridging fibrosis (18 of 26).²¹ This suggests that most cases of clinically acute AIH represent a flare of previously occult chronic disease. This idea was further supported by observations in a related study that found that patients with AIH of less than 3 months’ duration were indistinguishable by clinical and laboratory tests from patients with disease of at least 12 months’ duration.²² These findings support the view that AIH is an a priori chronic disease.¹

The histologic differential diagnosis of AIH is rather broad and depends on the clinical context of the affected patient. For patients who have severe, clinically acute hepatitis with prominent hepatocyte necrosis, the major differential diagnostic considerations include severe drug or toxic injury, fulminant A or B hepatitis, Epstein-Barr virus (EBV) (rare), and other types of systemic viral infection (see Table 47.3).

Distinguishing AIH from drug- or toxin-associated hepatitis can usually be accomplished by applying the principles of the scoring system of Alvarez and associates³ (see Table 47.2), which uses autoantibody status and hypergammaglobulinemia to establish a correct diagnosis. A thorough clinical history regarding use of drugs or toxins is essential.

In equivocal cases, a rapid response to immunosuppressive therapy helps support a diagnosis of AIH. Serologic testing for hepatitis A virus (HAV), hepatitis B virus (HBV), and EBV is usually quite reliable for distinguishing AIH and acute viral hepatitis. Acute hepatitis C is rarely a diagnostic concern, but when suspected, a positive serum assay result for hepatitis C virus (HCV) RNA is the best available diagnostic tool because anti-HCV antibodies may occur after the hepatitic episode. An initial absence of anti-HCV with subsequent development within weeks helps to support a diagnosis of acute hepatitis C infection.

Clinical Features and Epidemiology

Approximately 90% of patients with PBC are female and between the ages of 40 and 60 years (range, 20 to 80 years). PBC occurs worldwide, and all races are susceptible. There is some familial clustering of PBC, with daughters of affected mothers at highest risk, but overall, less than 1% of first-degree relatives of patients with PBC develop the disorder.³⁶ In a mostly white population in Olmsted County, Minnesota, the age-adjusted incidence of PBC is 4.5 and 0.7 per 100,000 women and men, respectively, with corresponding prevalence rates of 65.4 and 12.1 per 100,000.³⁷

PBC coexists with other autoimmune diseases, with the strongest associations with connective tissue disorders such as rheumatoid arthritis, CREST syndrome (calcinosis, Raynaud disease, esophageal dysmotility, sclerodactyly, and telangiectasia), systemic lupus erythematosus, dermatomyositis, interstitial lung disease, and autoimmune thyroid disease.³⁸ An association between celiac disease and PBC has been described.³⁹ However, these associations most likely represent clustering of diseases in patients who are prone to autoimmune conditions rather than a direct pathogenetic link.

In early stages, PBC is usually asymptomatic and is detected only by identification of abnormal serum liver test results. In early disease, elevated serum levels of alkaline phosphatase and γ-glutamyltransferase (GGT) are typical. Serum cholesterol levels are usually elevated, and serum bilirubin levels are usually normal or only minimally elevated (<2 mg/dL). Serum ALT and AST levels are usually normal or only mildly elevated. Serum immunoglobulin M (IgM) levels may be mildly elevated.

In more advanced disease, the same general biochemical patterns persist. However, bilirubin levels tend to rise progressively, and the biochemical stigmata of cirrhosis (i.e., decreased serum albumin, prolonged prothrombin time, and thrombocytopenia) eventually become apparent. In later stages, the signs and symptoms of disease may be divided into those related to progressive cholestasis and those related to cirrhosis. Among the former are pruritus, xanthomas, jaundice, and osteoporosis. The signs and symptoms of cirrhosis in PBC are the same as for other causes of cirrhosis: esophagogastric varices, ascites, spider angiomas, and splenomegaly.

Pathogenesis

There is strong evidence that PBC represents an autoimmune attack directed toward autoantigens on biliary epithelium. PBC is thought to be initiated when tolerance to the dihydrolipoyl transacetylase (E2) subunit of the pyruvate dehydrogenase complex (PDC-E2) is lost, resulting in development of PDC-E2 specific–AMAs.^33,40 The most conspicuous histologic features of PBC—lymphocytic and granulomatous destruction of intralobular and septal bile ducts—are tied to pathogenesis through the observation that intact immunoreactive PCD-E2 exists within apoptotic blebs of biliary epithelial cells.⁴¹ This protein has been demonstrated on allograft biliary epithelium in patients with recurrent PBC after liver transplantation.⁴²

Although characteristic of PBC, AMAs are detected by using standard immunofluorescence techniques in only 92% to 95% of patients with clinical and histologic features of PBC, and they can be seen in patients without the typical clinical and histologic features of this disorder.⁴³ ANAs are seen in approximately one third of patients, and the ANAs tend to be associated with a more rapid progression of disease.⁴⁴ Approximately 5% to 8% of PBC patients lack AMAs (i.e., AMA-negative PBC), also known as autoimmune cholangitis (AC).

The type of inflammation, the lymphocytic and granulomatous duct destruction, the associated autoimmune diseases of other organs, and occurrence of overlap syndromes of PBC and AIH provide strong support of PBC as an autoimmune disorder. The precise pathogenesis remains unknown. However, T cell–mediated cytotoxicity and molecular mimicry after infection likely play a central role.³³ Some have proposed a role for endothelin overproduction and biliary ischemia in the development of PBC.⁴⁵

Pathology

In early-stage PBC, the liver is often slightly enlarged and variably bile stained. In later stages, macronodular cirrhosis develops and is often associated with an intense green hue that reflects progressive cholestasis (Fig. 47.7). In contrast to PSC, cholangiectases and cholangitic abscesses are not seen.

The hallmark lesion of PBC is destructive cholangitis that affects interlobular and septal bile ducts and results in duct loss and subsequent biliary cirrhosis. The term nonsuppurative destructive cholangitis accurately describes these lesions, but the more succinct term florid duct lesion is more commonly used.⁴⁶ Because these lesions are usually focal, they may be missed on liver biopsy. The florid duct lesion is characterized by a portal lymphocytic infiltrate and epithelioid cells centered on septal and interlobular bile ducts, with histologic evidence of bile duct damage and destruction. Characteristic features include disruption of the bile duct basement membrane, intraepithelial lymphocytes and plasma cells, biliary epithelial cytoplasmic vacuolization, regenerative hyperplasia, and occasional mitotic figures. Granulomas are usually identified.

Florid duct lesions may reflect granulomatous duct destruction (Fig. 47.8) or more severe examples of lymphocytic cholangitis (Fig. 47.9). The bile duct damage in florid duct lesions is usually segmental in the longitudinal axis of the duct and in cross section, with only a portion of the duct affected at one time. Granulomas are often poorly defined and tend to be associated with the bile duct in an eccentric fashion, although concentric involvement may also be seen. Granulomas may also be found in portal lymphocytic infiltrates without an obvious connection to a bile duct. Less commonly, they may be found in hepatic lobules. With time, interlobular and septal bile ducts vanish, but small lymphohistiocytic aggregates may remain longer.

Bile duct changes are typically accompanied by a dense portal lymphoplasmacytic infiltrate (Fig. 47.10, A), which may be patchy in the early stages and may contain lymphoid aggregates and follicles, conspicuous plasma cells, and a few eosinophils.⁴⁷ Biliary damage is likely primarily caused by the T cell infiltrates, but B cells appear to participate, primarily in early stages.⁴⁸ When comparing AIH and PBC in terms of plasma cell subsets, IgG-positive cells strongly predominate over IgM-positive cells in AIH, but in PBC, IgM-positive plasma cells are much more conspicuous and may predominate.⁴⁹ The portal lymphocytic infiltrate may spill over into the lobules, mimicking the appearance of interface hepatitis (see Fig. 47.10, B). In rare cases, mild interface hepatitis with hepatocyte necrosis may also develop.

PBC lobules usually are almost normal. The normal-sized hepatocytes are not necrotic. In some cases, lymphocytes may aggregate within hepatic sinusoids in single-cell fashion, mimicking a lymphoproliferative disorder (Fig. 47.11, A). Scattered, usually small, noncaseating, lobular granulomas may be seen (see Fig. 47.11, B).

A subtle form of nodular regenerative hyperplasia has been observed in almost 50% of patients with early-stage disease. It may reflect portal venule damage by granulomas and contribute to the early development of portal hypertension.⁵⁰

The progression of early PBC to cirrhosis is divided into four histologic stages.⁵¹ Although florid duct lesions may be seen at any stage, they are most common in stages I and II (Table 47.8). Stage I (i.e., portal stage) is characterized by a portal lymphocytic infiltrate with or without a florid duct lesion. In stage II (i.e., periportal stage), added features include piecemeal necrosis and delicate periportal fibrosis, which is often associated with ductular proliferation. Stage III (i.e., septal stage) is characterized by bridging necrosis or fibrous septa, and stage IV fibrosis (i.e., cirrhotic stage) is associated with nodular regeneration.

Regenerative nodules in PBC and in PSC are usually not as regular and round as in other forms of cirrhosis. The nodules often have a garland-shaped, irregular outline, not unlike pieces of a jigsaw puzzle. A progressive loss of ducts may occur early in the course of disease, with ductopenia usually being prominent in stage III and almost complete in stage IV. Florid duct lesions become less common with advancing stage,⁵¹ presumably reflecting loss of the target biliary epithelium.

Periportal hepatocyte degeneration, which is thought to reflect bile acid (cholate) stasis, helps to distinguish PBC and PSC from chronic hepatitis resulting from autoimmune, viral, or drug causes.⁵² This feature becomes more prominent with advancing stages of disease and is similar in PBC and PSC. The finding of proliferating bile ductules at the limiting plate (Fig. 47.12, A and B) has been referred to as biliary piecemeal necrosis, in contrast to lymphocytic piecemeal necrosis that is typical of AIH.⁵³ Biliary piecemeal necrosis is often accompanied by feathery degeneration of periportal or paraseptal hepatocytes, Mallory bodies, and deposition of orcein-positive copper-protein complexes (see Fig. 47.12, C and D). The combined, low-magnification effect of these features is a characteristic halo-like pattern surrounding regenerative nodules (see Fig. 47.12, E).

Differential Diagnosis

PBC shares many histologic features with PSC. In liver biopsy specimens, they may be indistinguishable. Unfortunately, the pathognomonic florid bile duct lesion of PBC is less prevalent in late-stage disease, and the pathognomonic fibrous obliterative cholangitis lesion of PSC is typically focal and may not be sampled in needle biopsies of the liver. Portal inflammation usually is more intense in PBC than in PSC. PBC commonly demonstrates mild sinusoidal lymphocytosis, a feature not normally seen in PSC (Table 47.9; see Tables 47.3, 47.6, and 47.8).

Autoimmune Cholangitis

The term immunocholangitis was first used in Germany in 1987 to describe cases that resembled PBC histologically and clinically but had a serum autoantibody pattern similar to AIH.⁵⁷ These patients constitute 5% to 8% of those with phenotypic evidence of PBC.⁵⁸ In the mid-1990s, a number of publications addressed this issue, focusing primarily on the question of whether immunocholangitis should be considered AMA-negative PBC, an overlap syndrome with AIH, or a separate entity, such as AC^59–61 or autoimmune cholangiopathy.⁶²

It has become clear that AC is not equivalent to an AIH/PBC overlap syndrome. Comparison of the various clinical, histologic, and natural history aspects of PBC and AC indicates few differences between the two disorders.⁵⁸ The similar response rates of patients with AC or PBC to ursodeoxycholic acid (UDCA) therapy and a similar natural history of AC and PBC after liver transplantation support the concept that AC is a form of PBC.⁶³ The finding that most patients with AC show positive AMA levels when techniques more sensitive than standard indirect immunofluorescent microscopy are used further supports this theory.⁵⁸

Clinical Features and Epidemiology

Most patients with PSC are adults. Most are 20 to 40 years of age at diagnosis. When children are affected, approximately 35% also have features of AIH.^83,84 PSC occurs primarily in patients with idiopathic inflammatory bowel disease; 70% to 80% of patients with PSC also have chronic ulcerative colitis. Conversely, PSC develops in 2% to 7.5% of patients with ulcerative colitis and 1.4% to 3.4% of patients with Crohn’s disease.⁸³ Patients with the haplotypes HLA-A1, HLA-B8, HLA-DR3, HLA-DR4, and HLA-DRW52A are at increased risk.^85,86 In addition to its association with ulcerative colitis, other evidence of abnormal immune regulation in PSC includes the finding of perinuclear antinuclear cytoplasmic antibodies (pANCAs) in 80% of cases, antinuclear and smooth muscle antibodies in 20% to 50% of cases,⁸³ and an association with other autoimmune diseases, such as thyroiditis, diabetes, and AIH.

Serum tests often reflect a chronic cholestatic process. In the early stages, elevation of alkaline phosphatase and GGT levels is almost universal. Elevation in the serum cholesterol level is also common, but serum ALT and AST levels are often only mildly (two to three times normal) elevated or almost normal. Serum bilirubin levels are usually normal. While the disease progresses, bilirubin levels may become slightly elevated, and biochemical evidence of cirrhosis (e.g., thrombocytopenia and decreased serum albumin) may become apparent. Markedly elevated serum bilirubin levels may be found in advanced (stage IV) disease. If these levels are found in early-stage disease, the physician should consider a dominant large duct stricture (benign or malignant) or choledocholithiasis.

The hallmark of PSC is an abnormal cholangiogram. Endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP) show comparable accuracy.⁸³ With the exception of small duct PSC, cholangiography normally helps to establish the diagnosis by virtue of the characteristic, diffusely distributed, segmental, and multifocal strictures that lead to a beaded appearance with this radiologic test (Fig. 47.13).⁸⁷ Rarely, other conditions may show similar cholangiographic findings (see Differential Diagnosis).

Pathogenesis

The pathogenesis of PSC is uncertain. Similar to PBC, a combination of clinical, biochemical, and morphologic features indicates that PSC represents an immune-mediated attack on biliary epithelium. However, in contrast to PBC, in which the direct immune target seems to be biliary epithelium, damage to biliary epithelium is not apparent in early PSC. Concentric fibrosis is the dominant histologic feature. The absence of a response to immunosuppressive therapy suggests that PSC is not a straightforward autoimmune process.

Some authorities have speculated that progressive periductal fibrosis may lead to an interruption of fluid and nutrient exchange between the peribiliary capillary plexus and the bile duct epithelium,⁸⁷ which precipitates epithelial necrosis and eventually obliterates the lumen. The histologic changes in PSC are compatible with an immunologic attack on components of the subepithelial mesenchyme, leading to secondary fibrosis and possible ischemic epithelial damage.⁸⁸ Further evidence of a possible role for microvascular damage in PSC includes the morphologic similarity between PSC and ischemic cholangitis, particularly after liver transplantation,⁸⁹ and the observed displacement of peribiliary capillaries by connective tissue surrounding bile ducts in PSC.⁹⁰

Natural History

Survival among untreated patients with PSC depends on the stage of disease at the time of diagnosis and the degree of cholangiographically evident bile duct abnormality. Typical survival from the time of diagnosis to death or liver transplantation is 12 to 18 years. The degree of cholangiographic disease is inversely correlated with survival.^91,92

The course of progression has been assessed through examination of paired biopsy samples.⁹³ Among patients with stage II disease, progression occurred in 42%, 66%, and 93% of patients at 1, 2, and 5 years, respectively. Among those with stage III disease, progression occurred in 14%, 25%, and 52%, respectively. Patients with PSC have a 4% to 14% risk for cholangiocarcinoma,⁹⁴ which is associated with an extremely poor prognosis.⁹⁵ Patients with small duct PSC, which is associated with a more favorable course than classic PSC, have a survival rate comparable to the general population and have a lower risk of hepatobiliary malignancy.⁹⁶

Several mathematical models for predicting survival in PSC independent of biopsy have been developed. They are based on serum bilirubin, AST, and albumin levels and on the presence or absence of variceal bleeding,⁹¹ specific cholangiographic findings,⁹² and patient age at diagnosis.⁹⁶

Pathology

In early-stage disease, the liver is often slightly enlarged and bile stained to some degree. In later stages, similar to PBC, a macronodular type of cirrhosis develops that may be intensely green, reflecting progressive cholestasis (Fig. 47.14, A). In contrast to PBC, cholangiectases and cholangitic abscesses may develop. Cholangiectases are recognizable as cystic collections of bilious, sometimes calculous, dark green material that may be several centimeters in diameter, and they are usually located in the hilar region of the liver (see Fig. 47.14, B). Cholangitic abscesses, which presumably reflect superinfection of cholangiectases, have a more yellow appearance than cholangiectases (see Fig. 47.14, C). The large intrahepatic and extrahepatic ducts may develop areas of gross stricture and concentric fibrosis. Cholangiocarcinoma and bile duct carcinoma are recognizable as firm, white, sclerotic lesions or masses.

Large Ducts

Biopsies of the extrahepatic bile ducts in PSC usually reveal a thickened, fibrotic wall with a mixed inflammatory infiltrate. However, these alterations are nonspecific, because strictures unrelated to PSC (e.g., after bile duct surgery, after passage of gallstones with associated duct damage) may have similar features. Alterations of large intrahepatic ducts mimic those in the extrahepatic ducts. Both types of ducts may show segmental fibrosis with stricture formation. Areas of stricture frequently alternate with cholangiectases and occasional cholangitic abscesses.

Histologic examination of cholangiectases reveals duct dilatation, epithelial atrophy with focal denudation, and mixed bilious material, neutrophils, and granulation tissue at the site of denudation (Fig. 47.15, A). Cholangitic abscesses are similar, but they tend to have a more exuberant neutrophilic infiltrate (see Fig. 47.15, B). Although these lesions strongly suggest PSC, they are rarely seen in liver biopsy samples.

Liver

The hallmark lesion of PSC is fibrous cholangitis, which may affect large ducts (perihilar intrahepatic or extrahepatic) and small intrahepatic bile ducts. When PSC affects small intrahepatic ducts without large duct involvement, small duct PSC may be diagnosed.⁹⁷ Fibrous cholangitis is characterized by a mixed inflammatory infiltrate within or adjacent to damaged bile ducts associated with extensive concentric collagen deposition, which appears as a fibrous collar surrounding the duct combined with atrophy of the epithelium (Fig. 47.16, A and B). These lesions are frequently focal.

The end stage of fibrous cholangitis, sometimes referred to as fibrous-obliterative cholangitis, is characterized by complete loss of epithelium and the formation of fibrous scars that may be the only evidence of a preexisting bile duct (see Fig. 47.16, C and D). Unfortunately, fibrous-obliterative cholangitis is a rare finding among liver biopsy specimens. Ductopenia without ductal scars is the most common bile duct finding in needle biopsies from patients with advanced PSC.

With time, PSC proceeds through various histologic stages, similar to PBC (see Tables 47.3 and 47.8).⁹⁸ Stage I disease is characterized by the presence of portal edema, inflammation, and ductular proliferation. At this stage, the changes may be indistinguishable from those of incomplete, secondary large duct obstruction, or they may resemble stage I PBC. Stage II is characterized by periportal fibrosis and inflammation with or without ductular proliferation. Scant lymphocytic piecemeal necrosis may be seen in some cases. In stage III disease, fibrous septa extend between adjacent portal tracts, and ductopenia becomes more prominent. Biliary piecemeal necrosis and cholate stasis, changes identical to those described in PBC, may become apparent (see Fig. 47.12, A through E). Similar to PBC, stage IV disease is the cirrhotic stage and is characterized by garland-shaped, regenerative nodules usually accompanied by ductular and biliary piecemeal necrosis that forms halos around the periphery of the nodules. Tissue samples often show near-complete loss of interlobular bile ducts at this stage.

Differential Diagnosis

The differential diagnosis of PSC includes histologic and cholangiographic categories, with some diagnoses spanning both classifications (Table 47.10; see Table 47.6). Histologic mimics have similarities in the pattern of inflammation or bile duct damage.

Clinical Features

In obstructive cholangitis (i.e., large duct obstruction), mechanical interruption of extrahepatic bile flow caused by biliary stones within large ducts or the bile duct, ampullary strictures, or masses may produce a clinical and histologic picture that depends on the time frame (acute or chronic) and degree of stenosis (partial or complete obstruction). Nausea and vomiting are common early symptoms. Jaundice typically develops in cases of severe obstruction. Common duct obstruction with secondary (ascending) cholangitis may elicit the Charcot triad of symptoms (i.e., right upper quadrant pain, fever, and jaundice), with additional hypotension and mental status changes resulting in the Raynaud pentad, a poor prognostic sign. In patients with chronic, low-grade obstruction, progressive hepatic fibrosis and chronic biliary-type cirrhosis may evolve with the development of progressive pruritus and other consequences of established cirrhosis (e.g., portal hypertension, coagulopathies). Biochemically, acute bile duct obstruction is usually associated with a significant elevation in serum aminotransferase (ALT and AST), alkaline phosphatase, and GGT levels, with hyperbilirubinemia in proportion to the degree of obstruction but not often exceeding 25 mg/dL. In patients with chronic bile duct obstruction, serum aminotransferase levels tend to decrease, and alkaline phosphatase and GGT levels persist or slowly increase.

Pathology

Obstructive cholangitis does not have specific gross pathologic features. Histologically, liver biopsies from patients with acute bile duct obstruction may show portal edema, ductular proliferation with neutrophils (i.e., cholangiolitis), tortuous bile ducts that may appear increased in number on histologic sectioning, and, in some cases, intraluminal or intraepithelial bile duct neutrophils (i.e., cholangitis). Bile pigment may accumulate within the bile duct lumens and be visible on histologic examination. Even in the acute stage of extrahepatic large duct obstruction, the pathologist often notices a temporal progression of histologic changes. For instance, within the first 1 to 2 weeks of obstruction, cholestasis begins in the zone 3 (perivenular) region, which is often associated with portal edema and portal inflammation. In this early acute period, the pattern of cholestasis may mimic a drug effect, infectious hepatitis, or sepsis or shock.

Cholestasis in the early phase is often intracytoplasmic and canalicular with occasional large bile plugs. Thereafter, a marked marginal bile ductular reaction associated with neutrophils (i.e., cholangiolitis) develops in more than 80% of cases. In the following weeks and with continued obstruction, the parenchymal and portal changes become more developed, and cholestasis becomes more pronounced. Cholestasis extends to zone 2 and zone 1 (periportal) regions, the deposits become larger in size and number, and cholestatic liver cell rosettes associated with dense bile concretions may develop. Cholestatic feathery degeneration is common: hepatocytes are enlarged, rarefied, and degenerated. Lyses of liver cells and release of bile leads to the formation of bile lakes and bile infarcts, which are defined as clusters of confluent liver cells with feathery degeneration, bile stasis, and necrosis with or without macrophages. These features are virtually diagnostic of obstructive cholangitis. Bile infarcts are caused by the toxic action of bile salts. With repair, foreign-body giant cells and fibrous tissue become apparent.

If the obstructive cause is not reversed in the acute period, chronic changes develop, including further cholate stasis, copper accumulation, Mallory bodies, fibrosis, and cirrhosis. The bile ductular reaction may become extremely prominent. Eventually, a process resembling SSC develops. The small and large interlobular bile ducts show proliferation, branching, and increased tortuosity. The epithelium may appear degenerated or ulcerated, resulting in periductal fibrosis. Ductular proliferation is usually prominent. Canalicular cholestasis, often pericentral (zone 3) predominant, may be seen in severe cases (Fig. 47.22, A). Eventually, persistent chronic obstruction (Fig. 47.23) may result in a biliary cirrhosis–like histologic appearance, except that the bile ducts usually persist.

Differential Diagnosis

The major differential diagnosis for acute bile duct obstruction is cholestatic drug injury. In some cases, knowledge of the clinical features is needed to establish a correct diagnosis. The histiologic features that favor bile duct obstruction include portal edema, zone 3 canalicular cholestasis, and acute cholangitis with bile accumulation within the lumens of the bile ducts. Drug reactions may also cause zonal cholestasis but not usually prominent edema. Cholestasis associated with systemic shock or sepsis (i.e., cholangitis lenta) tends to cause the formation of bile plugs in dilated zone 1 (periportal) cholangioles, which contrasts with drug reactions and acute bile duct obstruction. Nevertheless, all of these disorders may show brisk ductular proliferation with or without neutrophils.

For chronic biliary tract obstruction, the major differential diagnoses are chronic ductopenic syndromes (i.e., PBC, PSC, and SSC). All of these disorders show progressive biliary-type fibrosis and cholate stasis. However, in contrast to PBC, PSC, and SSC, bile ducts usually persist and remain viable in cases of chronic biliary tract obstruction. All of these disorders, including chronic bile duct destruction, may show some degree of ductular proliferation at the portal-parenchymal interface (i.e., limiting plate).