Cholestatic Liver Disease and Biliary Tract Disease
Jason Lewis, MD
13.1 INTRODUCTION
Cholestasis is defined as impaired bile flow. It may be secondary to either hepatocyte abnormalities or compromise of the biliary tree.1 From an etiologic perspective, compromise of the biliary tree can be primary or secondary, and from an anatomic standpoint either intra- and/or extrahepatic. Biliary tract compromise typically leads to a characteristic constellation of portal-based changes (see below).1
Clinically, cholestasis is characterized by hyperbilirubinemia and an elevated alkaline phosphatase and γ-glutamyltransferase (GGT). Because GGT can be elevated in other conditions, alkaline phosphatase is the more specific indicator. Importantly, clinical and histologic cholestasis may not occur simultaneously. It is not uncommon for there to be an elevated alkaline phosphatase with no histologic features of cholestasis.
There are five elements to assess when considering a diagnosis of cholestatic or chronic biliary disease. The combination of these features will vary with the type and stage of disease.
1. Cholestasis: Bile can be identified in hepatocytes, Kupffer cells, canaliculi, proliferative bile ductules, or bile ducts (Fig. 13.1). Cholate stasis is the term given to the cytologic changes which occur in
hepatocytes secondary to the toxic effects of retained bile: cytoplasmic swelling with protein condensation (feathery degeneration) and Mallory-Denk bodies (Figs. 13.2 and 13.3).1 In severe cases, foci of hepatocyte necrosis with extravasated bile can be seen, which is referred as bile infarcts. In chronic biliary disease, cholestasis is typically not seen until late in the course of the disease.
hepatocytes secondary to the toxic effects of retained bile: cytoplasmic swelling with protein condensation (feathery degeneration) and Mallory-Denk bodies (Figs. 13.2 and 13.3).1 In severe cases, foci of hepatocyte necrosis with extravasated bile can be seen, which is referred as bile infarcts. In chronic biliary disease, cholestasis is typically not seen until late in the course of the disease.
 Figure 13.1 Cholestasis. Canaliculi are not visible under normal circumstances but can be seen in cholestasis when they become dilated with inspissated bile plugs. |
2. Ductular reaction: A reactive process that consists of a mixture of ductular proliferation, inflammation, and stromal cells along the limiting plate.2 Ductular reactions can occur in many types of disease, and the morphology does not always indicate the precise cause.2 It may be seen as a secondary pattern in cases of fulminant necrosis or chronic hepatitis in which it is accompanied by other significant portal and lobular changes.2 Conversely, a primary injury pattern of ductular reaction is one of the earliest and most sensitive indicators of bile flow impairment. With obstruction,
there is a visible proliferation of ductules along the perimeter of the portal tracts (Figs. 13.4 and 13.5). The lumina of the ductules are typically not visualized unless they are expanded by bile plugs. Bile plugs within ductules (ductular or cholangiolar cholestasis) is termed cholangitis lenta. Although this pattern may be seen in late stage chronic biliary disease, it is also present in other conditions such as sepsis, shock, or uremia (Figs. 13.6 and 13.7).2 When the obstruction is acute onset and involves a large duct, ductular reaction is typically accompanied by portal edema. With chronicity, the edema subsides and is replaced by fibrosis.2 Inflammatory cells, including lymphocytes, plasma cells, and neutrophils, are an integral component of ductular reaction. The presence of neutrophils along the limiting plate can serve as a valuable clue to the presence of ductular reaction.
there is a visible proliferation of ductules along the perimeter of the portal tracts (Figs. 13.4 and 13.5). The lumina of the ductules are typically not visualized unless they are expanded by bile plugs. Bile plugs within ductules (ductular or cholangiolar cholestasis) is termed cholangitis lenta. Although this pattern may be seen in late stage chronic biliary disease, it is also present in other conditions such as sepsis, shock, or uremia (Figs. 13.6 and 13.7).2 When the obstruction is acute onset and involves a large duct, ductular reaction is typically accompanied by portal edema. With chronicity, the edema subsides and is replaced by fibrosis.2 Inflammatory cells, including lymphocytes, plasma cells, and neutrophils, are an integral component of ductular reaction. The presence of neutrophils along the limiting plate can serve as a valuable clue to the presence of ductular reaction.
 Figure 13.2 Cholestasis. Bile pigment can be identified as golden granular material within hepatocytes or as phagocytosed debris within Kupffer cells. Cholate stasis is characterized by feathery degeneration (cytoplasmic swelling with protein condensation) of hepatocytes. Mallory-Denk bodies are often present. |
 Figure 13.3 Cholestasis. Cholate stasis preferentially affects periportal and periseptal hepatocytes. |
 Figure 13.4 Ductular reaction. Marked ductular reaction characterized by an irregular mass of ductules along the limiting plate and focally extending into the periportal lobule. No well-formed lumina are seen in this field. Neutrophilic pericholangitis is present. Note the cholate stasis within the periportal hepatocytes to the left. |
 Figure 13.5 Ductular reaction. Ductular reaction is not always pronounced. In the center of the field, there is a subtle ductular reaction extending vertically along the interface of the lobule and the portal tract. There is a poorly formed lumen present within one of the ductule profiles. |
 Figure 13.6 Cholangitis lenta. Cholangitis lenta in a case of sepsis. Proliferating ductules along the perimeter of the portal tract are dilated and contain inspissated bile plugs (ductular or cholangiolar cholestasis). There is no significant fibrosis. This finding is often idiopathic but can also be seen in shock, uremia, or any debilitating illness. |
 Figure 13.7 Ductular cholestasis. Ductular cholestasis is seen in this case of primary biliary cirrhosis. With prolonged cholestasis of any etiology, bile plugs can be seen within the proliferating ductules. This finding is most commonly seen in the setting of end-stage disease and clinical decompensation. |
3. Ductopenia: Ductopenia is defined as the absence of a bile duct branch in at least 50% of portal tracts.3 The number of portal tracts needed for an adequate specimen varies by institution. From a practical standpoint, 8 to 10 portal tracts are usually sufficient to determine if there is significant ductopenia. Because the bile duct branch travels with the hepatic artery, the presence of an artery without a bile duct is a helpful indicator of bile duct loss within that portal tract3 (Fig. 13.8). Normally, 70% to 80% of arteries have an associated bile duct.3 At times, portal inflammation may be so dense that it is difficult to identify normal structures. Cytokeratin 7 (CK7) immunostains can aid by highlighting ducts in this situation. Though not typically utilized for this purpose, periodic acid-Schiff diastase (PASD) highlights the basement membranes of bile ducts and can be used to assess for ductopenia. Table 13.1 contains a list of disease processes which can result in ductopenia.
 Figure 13.8 Ductopenia. The portal tract contains a portal vein and hepatic artery branch but no bile duct. |
4. Copper accumulation: In early stage disease, the presence of periportal copper is highly suggestive of a chronic biliary disease. Though rare in chronic hepatitis and steatohepatitis, copper accumulation can be found in a small percent of these cases when there is advanced fibrosis (<10%).4 In chronic biliary disease, the amount of copper increases with the stage of the disease, such that the absence of copper in the cirrhotic liver is unusual for chronic biliary disease (Figs. 13.9 and 13.10).4 At Mayo Clinic, rhodanine stain is performed on 10-um thick sections. The orcein stain for copper-associated protein is another commonly utilized stain at other medical centers.
5. Fibrosis: Chronic biliary disease has a characteristic pattern of scarring, termed jigsaw puzzle-like, in which there is an irregular shape to the cirrhotic nodules (Fig. 13.11). In addition, fibrosis is often unevenly distributed within the liver in early stage disease. When present, fibrosis of any degree
indicates a chronic disorder and argues against an acute process, such as a cholestatic drug reaction or acute large duct obstruction.
indicates a chronic disorder and argues against an acute process, such as a cholestatic drug reaction or acute large duct obstruction.
Table 13.1 Common causes of ductopenia in adults | |
|---|---|
|
 Figure 13.9 Rhodanine stain. In this case of primary biliary cirrhosis, the copper appears as rust-colored granules within hepatocytes. The amount of copper generally increases with the stage of disease and the severity of cholestasis. |
 Figure 13.10 Rhodanine stain. In early cholestatic liver disease, copper deposits can be very focal, identified in only rare periportal hepatocytes, requiring careful high-power examination. |
 Figure 13.11 Biliary pattern of cirrhosis. In this case of end-stage primary sclerosing cholangitis, there is an irregular pattern of scarring such that the lobular parenchyma appears to fit together like pieces of a puzzle, hence the term jigsaw puzzle-like. This pattern is not universally present, and some cases may demonstrate more classic regenerative nodules. |
Older scoring systems for chronic biliary disease did not give a separate grade and stage for the disease. Instead, inflammation and fibrosis were combined into an overall staging system. For example, the one used historically at the Mayo Clinic was created by Ludwig et al.5:
Stage 1: Portal stage—all disease activity is confined to the portal tract; limiting plate intact.
Stage 2: Periportal stage—limiting plate disrupted by lymphocytic interface activity and/or ductular reaction; portal tracts have irregular shape.
Stage 3: Septal stage—fibrous septa (portal-portal bridging fibrosis).
Stage 4: Cirrhotic stage—fibrous septa and parenchymal distortion.
These staging systems are not widely used anymore, but can be encountered in older pathology reports on prior specimens. Currently, at the Mayo Clinic and at most medical centers, fibrosis in biliary tract disease is staged using a standard system such as the Batts-Ludwig, Ishak, or Metavir.
The majority of this chapter will focus on the three main causes of primary chronic biliary tract disease: primary biliary cirrhosis, primary sclerosing cholangitis, and Immunoglobulin G4 (IgG4)-related disease (Table 13.2), followed by brief discussions of secondary causes.
Table 13.2 Clinicopathologic features of the three major autoimmune cholangiopathies | ||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
13.2 PRIMARY BILIARY CIRRHOSIS
Definition
Primary biliary cirrhosis is an autoimmune disease targeting the small, intrahepatic bile ducts.
Clinical features
Primary biliary cirrhosis preferentially affects middle age women (90% of patients are female; median age at diagnosis 50 years).6, 7, 8, 9 It is not diagnosed in children.10 More than half of patients are asymptomatic at the time of diagnosis and are identified on screening or workup of other conditions.7,11,12 When present, fatigue and pruritus are the most common symptoms.7 Fatigue can occur in up to 78% of patients, and pruritus in 20% to 70%, over the course of the disease.7 It is often associated with other autoimmune conditions, including Sjogren syndrome, scleroderma, celiac disease, and hypothyroidism.7
Primary biliary cirrhosis should be ruled out in any patient with a chronic, unexplained elevation in alkaline phosphatase, particularly in middle-age women. Diagnostic criteria include two of the following three findings: (1) chronic elevation of alkaline phosphatase; (2) positive antimitochondrial antibody (AMA); and (3) characteristic histologic features.13 A liver biopsy is not required in the majority of cases. It is typically performed to diagnose AMA-negative primary biliary cirrhosis (see below), rule out an overlap syndrome or superimposed process, and for staging purposes.
Laboratory findings
Primary biliary cirrhosis is characterized biochemically by elevated alkaline phosphatase levels. Mild elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are also usually present, but the alkaline phosphatase levels are disproportionately elevated.13 The AMA is the serologic hallmark of primary biliary cirrhosis, present in 90% to 95% of patients and in less than 1% of the general population.7,13 AMA may be identified years before the disease manifests clinically.7 The M2 subtype is
the most sensitive and specific.14 At Mayo Clinic, an enzyme immunoassay is used to detect AMA-M2 autoantibodies. Roughly half of patients will be antinuclear antibody (ANA) and antismooth muscle antibody (ASMA) positive.7,15
the most sensitive and specific.14 At Mayo Clinic, an enzyme immunoassay is used to detect AMA-M2 autoantibodies. Roughly half of patients will be antinuclear antibody (ANA) and antismooth muscle antibody (ASMA) positive.7,15
Imaging
Imaging studies are used to exclude obstructive processes within the biliary tree.
Gross findings
Liver explants show end-stage cirrhosis with a biliary pattern. The liver can be enlarged or mildly atrophic and shows a dark green color because of cholestasis. The cirrhosis usually shows a mixed micro and macronodular pattern.
Microscopic findings
General features
In 1965, the term chronic nonsuppurative destructive cholangitis was suggested as an alternative to primary biliary cirrhosis because it “accurately describes the basic lesion and has the further merit of avoiding the term cirrhosis.”16,17 Two years later this “basic lesion” was termed the florid duct lesion, which is the histologic hallmark of primary biliary cirrhosis.17 For unknown reasons, the inflammatory injury preferentially affects intrahepatic bile ducts measuring less than 80 to 100 microns in diameter.16, 17, 18, 19, 20, 21, 22
The florid duct lesion is the histologic manifestation of inflammatory duct destruction (Figs. 13.12, 13.13, and 13.14). It is defined by the presence of both granulomatous inflammation and bile duct damage.14,16,17,23, 24, 25 The inflammatory component comprises lymphocytes, plasma cells, and histiocytes. Lymphocytes may be quite dense, forming aggregates around the bile ducts.16,17,23 They characteristically infiltrate into the biliary epithelium (lymphocytic cholangitis). The granulomatous component is directed toward the bile duct or is in close proximity, not merely present in the portal tract. It may be well-formed or consist of loose aggregates of macrophages.16,23,25,26 Bile duct damage manifests as cytologic injury to the biliary epithelial cells and/or disruption of the bile duct basement membrane.11,16,23,25
Needle biopsy findings
Florid duct lesions are patchy in the liver parenchyma and may not be sampled in needle biopsies. In addition, they decrease in frequency with progression of disease.5,18 For example, Ludwig et al. identified florid duct lesions in 38% to 45% of early stage (1 or 2) biopsies but only 15% to 19% of late stage (3 or 4) biopsies.5
 Figure 13.12 Primary biliary cirrhosis. The bile duct in the center of the field is encircled by granulomatous inflammation. A relatively dense aggregate of lymphocytes is visible along the right edge. Note how lymphocytes invade through the basement membrane and infiltrate into the bile duct epithelium (lymphocytic cholangitis). The lymphocytes are surrounded by a clear halo and are more hyperchromatic than the biliary nuclei. There is cytoplasmic swelling of some epithelial cells indicative of injury. |
 Figure 13.13 Primary biliary cirrhosis. An example of primary biliary cirrhosis in which the granulomatous inflammation is poorly-formed. Lymphocytic cholangitis with destruction of the duct is well-developed. There is rupture of the basement membrane and the biliary nuclei have a disorganized, jumbled appearance along with mild pleomorphism. |
In the appropriate clinical setting (positive AMA and elevated alkaline phosphatase), the presence of patchy, portal-based lymphoplasmacytic inflammation is sufficient to render the diagnosis of “consistent” or
“compatible with” the clinical diagnosis of primary biliary cirrhosis, after drug effect has been excluded. After making a diagnosis of primary biliary cirrhosis, attention should next be focused on excluding other disease processes (e.g., steatohepatitis) and accurate staging.
“compatible with” the clinical diagnosis of primary biliary cirrhosis, after drug effect has been excluded. After making a diagnosis of primary biliary cirrhosis, attention should next be focused on excluding other disease processes (e.g., steatohepatitis) and accurate staging.
 Figure 13.14 Primary biliary cirrhosis. Plasma cells can be conspicuous. This finding does not necessitate a diagnosis of primary biliary cirrhosis-autoimmune hepatitis overlap. |
Pertinent findings by disease stage
While disease stages do not correlate exactly with fibrosis stages, they nicely organize the various findings in primary biliary cirrhosis and can be useful for illustrating disease progression
Stage 1: Nascent primary biliary cirrhosis is portal-based, and this can be appreciated at low-power scanning magnification in which a subset of portal tracts contain dense, lymphocytic infiltrates with occasional plasma cells and lymphoid aggregates (Fig. 13.15). Granulomatous cholangitis (florid duct lesion) is common but may be focal, with some normal-appearing portal tracts and some demonstrating only lymphocytic cholangitis. Ductopenia is not seen in this stage. Cholestasis is absent. Lobular inflammation is usually absent or mild, but small granulomas may occasionally be present. A fraction of cases may show focal periportal copper.
Stage 2: Portal tracts show a ductular reaction, often with interface activity (Fig. 13.16). Florid duct lesions may be identified. Some portal tracts may lack intact bile ducts. Cholestasis is rarely seen. Periportal copper accumulation is present in the majority of cases and is moderate in a small percent.
Stage 3: Trichrome stain shows portal-portal bridging fibrosis. Inflammation diminishes and florid duct lesions are less common. Ductular reactions persist and hepatocanalicular cholestasis increases. Ductopenia may be present. There is moderate copper accumulation in the majority of cases.
 Figure 13.15 Primary biliary cirrhosis. Low-power example of stage 1 primary biliary cirrhosis. Note how there is a dense, portal-based lymphoid aggregate visible at scanning magnification. Even at this power, the process appears confined to the portal tract and the lobule appears quiescent. |
 Figure 13.16 Primary biliary cirrhosis. In stage 2 primary biliary cirrhosis, there is eventually disruption of the limiting plate by ductular reaction. Some degree of inflammation may be present, including rare apoptotic hepatocytes. |
Stage 4: The Trichrome stain shows a biliary type of cirrhosis. Ductular reactions may be prominent and there can be marked cholestasis and cholate stasis within periportal hepatocytes (Fig. 13.17). Ductopenia is well-developed and copper deposition is present in essentially all cases, being extensive in approximately half.
 Figure 13.17 Primary biliary cirrhosis. End-stage primary biliary cirrhosis is characterized by exuberant ductular reaction and hepatocanalicular cholestasis. However, the findings are not specific at this stage. There is abundant bile pigment within hepatocytes and Kupffer cells. |
Primary biliary cirrhosis variants
AMA-Negative primary biliary cirrhosis
About 5% to 10% of patients will have typical clinical and pathologic features of primary biliary cirrhosis, except for a negative AMA.13 These individuals are more likely to have positive ANA/ASMA and lower immunoglobulin M (IgM) levels than AMA-positive patients.13 The natural history of their disease and response to ursodeoxycholic acid (UDCA) are similar to AMA-positive patients.13,27, 28, 29
Given the absence of AMA, a liver biopsy is required for the diagnosis.13 Histologic findings, including florid duct lesions and periportal copper accumulation, are similar to AMA-positive cases.28 Granulomatous cholangitis provides the strongest histologic corroboration of primary biliary cirrhosis.13
Primary biliary cirrhosis-autoimmune hepatitis overlap
Rendering the diagnosis of primary biliary cirrhosis-autoimmune hepatitis overlap is challenging because of the variability in diagnostic criteria and the clinical, biochemical, and histologic overlap.10,13 In one practical approach that combines laboratory and histologic findings, overlap is suggested if 2 of the following 3 features are identified in a patient with primary biliary cirrhosis: (1), ALT > 5 times upper limit of normal; (2), immunoglobulin G (IgG) > 2 times upper limit of normal and/or a positive ASMA; and (3), moderate or severe interface activity.13,30 This approach is most commonly used by clinicians. An overlap syndrome can be suggested by pathology findings when there is more lobular hepatitis than is typically seen in primary biliary cirrhosis, in particular at the moderate or marked levels. Primary biliary cirrhosis and autoimmune hepatitis can be diagnosed concurrently or sequentially.10,30,31 Because of the lack of uniform diagnostic criteria, the prevalence of overlap varies by study, ranging from 1% to 9%.10,30
It has been this author’s anecdotal experience that the typical scenario is one in which a patient has a known history of primary biliary cirrhosis (+AMA) and is then found to have prominent elevations in transaminase levels. Because >30% of primary biliary cirrhosis patients may have a positive ANA, this test is not discriminatory.7,10 Therefore, a biopsy is undertaken to determine if any histologic features of autoimmune hepatitis are present: specifically to determine the severity of interface and lobular necroinflammatory activities.
As noted above, plasma cells are present in typical cases of primary biliary cirrhosis and are not, in and of themselves, sufficient to suggest an overlap syndrome. Considering that interface activity is also commonly seen in primary biliary cirrhosis, it becomes clear that it would be extremely difficult to diagnose a superimposed minimally or mildly active autoimmune hepatitis (grade 1 or grade 2). For cases of primary biliary cirrhosis that have morphologic features suggestive of, but not diagnostic for, autoimmune hepatitis, the pathology reports can mention that the possibility of an overlap syndrome cannot be ruled out but it is not the predominant component of the liver disease. The clinicians will decide to start corticosteroid therapy or not based on the overall clinical findings.
In typical cases of overlap syndrome, the ALT levels are moderately to severely elevated.13 Correspondingly, the biopsy shows moderate to severe levels of interface and lobular necroinflammatory activity (grades 3 or 4) or confluent lobular necrosis (grade 4) (Figs. 13.18 and 13.19).13,28,30 If the patient has been on disease modifying treatment (e.g., corticosteroids), then the diagnostic features of an overlap syndrome may be less evident, a point that can be conveyed in the pathology report.
Immunohistochemistry and special stains
CK7 immunostains can be used to identify interlobular bile ducts and evaluate for ductopenia in cases with marked portal inflammation. They will also highlight
intermediate hepatocytes when there is chronic cholestatic injury. The rhodanine stain for copper is also a useful ancillary test to support the impression of a chronic biliary disease, as it will show patchy deposition of copper in the periportal hepatocytes.
intermediate hepatocytes when there is chronic cholestatic injury. The rhodanine stain for copper is also a useful ancillary test to support the impression of a chronic biliary disease, as it will show patchy deposition of copper in the periportal hepatocytes.
 Figure 13.18 Primary biliary cirrhosis-autoimmune hepatitis overlap. Transaminase levels in this well-established case of PBC flared to >10× upper limit of normal. Note the well-developed plasmacytic interface activity within the upper central aspect of the field. |
 Figure 13.19 Primary biliary cirrhosis-autoimmune hepatitis overlap. Elsewhere within the biopsy were numerous foci of lobular inflammation, like these pericentral aggregates of plasma cells. Marked cholestasis, manifested by collections of macrophages containing phagocytosed bile pigment, was also present. |
Immunostains for IgG and IgM can be helpful in difficult cases to distinguish primary biliary cirrhosis from autoimmune hepatitis. The plasma cells in primary biliary cirrhosis are predominantly positive for IgM (equal or greater in number than IgG-positive plasma cells), whereas autoimmune hepatitis is characterized by predominant IgG-positive plasma cells.32, 33, 34 The same portal tracts should be compared when using these stains. Immunostains for Langerhans cells, such as CD1a or Langrin, can also be helpful in diagnosing primary biliary cirrhosis, showing an increased number of intraepithelial Langerhans cells in the bile ducts.35
Differential diagnosis
Chronic hepatitis
Chronic hepatitis of viral or autoimmune etiology is characterized by portal-based inflammatory infiltrates which may be very dense and look similar to early stage primary biliary cirrhosis on low power. Although not characteristic, roughly one-fourth of liver biopsies from patients with autoimmune hepatitis can demonstrate biliary changes, including lymphocytic cholangitis or ductopenia.8 Similarly, bile duct damage has been described in approximately one-third of chronic hepatitis C cases.36 On the other hand, lymphocytic interface activity also occurs in primary biliary cirrhosis. These challenges can be sorted out by careful attention to clinical, laboratory, and histologic findings. Serologic studies are diagnostic in most viral hepatitis cases, though in acute viral infections nucleic acid testing may be needed. Histologically, the major pattern of injury can help clarify the diagnosis. For example, the presence of well-developed florid duct lesions with only a mild degree of interface and lobular inflammation would support the diagnosis of primary biliary cirrhosis. In contrast, prominent lymphoplasmacytic inflammation with moderate interface and lobular activity, but only focal bile duct injury, suggests autoimmune hepatitis. Confluent lobular necrosis, seen with more severe lobular activity, is also not typical of primary biliary cirrhosis and suggests chronic hepatitis of viral or autoimmune etiology.
Sarcoidosis
Though patients are typically clinically asymptomatic for liver disease, sarcoidosis commonly involves the liver, with granulomas identifiable in 50% to 70% of specimens.37,38 When a biopsy is performed for biochemically evident liver disease, granulomas are almost universally present.39 The granulomatous inflammation can be associated with a cholestatic, hepatitic, or vascular pattern of injury.39 Some features may overlap with primary biliary cirrhosis, including
granulomatous cholangitis, hepatocanalicular cholestasis, ductopenia, and copper accumulation.39 Fibrosis may be present and extensive in some cases.39
granulomatous cholangitis, hepatocanalicular cholestasis, ductopenia, and copper accumulation.39 Fibrosis may be present and extensive in some cases.39
Sarcoidosis usually affects younger patients than primary biliary cirrhosis and lacks the strong female predilection.37 Negative serology for AMA, normal IgM serum levels, and the presence of extrahepatic granulomas support the diagnosis of sarcoidosis.38
Sarcoid granulomas are typically more numerous than the granulomas in primary biliary cirrhosis. In addition, they are usually well-formed, often contain multinucleated giant cells, and may have associated fibrosis (Figs. 13.20, 13.21, and 13.22). While they are characteristically found in the portal tracts, they are often identified in the lobular parenchyma as well. In some cases, the granulomas coalesce to form tumefactive nodules apparent at low power. In contrast, the granulomas in primary biliary cirrhosis can be either poorly- or well-formed, tend to be smaller, and lack fibrosis.
 Figure 13.20 Sarcoidosis. Granulomas of sarcoidosis are often tumefactive and readily apparent on low-power inspection. Unlike in primary biliary cirrhosis, giant cells are typically numerous. |
 Figure 13.21 Sarcoidosis. Note how the granulomatous component in the right aspect of the field is not centered on the bile duct, as in primary biliary cirrhosis. |
 Figure 13.22 Sarcoidosis. Granulomas are often present throughout the lobule, not just within the portal tracts. |
Primary sclerosing cholangitis
Primary biliary cirrhosis and primary sclerosing cholangitis can be distinguished in many cases by serology and imaging studies. The primary situation that can cause diagnostic difficulty from a clinical standpoint is differentiating AMA-negative primary biliary cirrhosis (5% to 10% of cases) from small duct primary sclerosing cholangitis (5% of cases). In early stage disease, primary biliary cirrhosis demonstrates more prominent portal inflammation, often with dense lymphoid aggregates.40 Florid duct lesions support the diagnosis of primary biliary cirrhosis. Although granulomas can rarely be seen in primary sclerosing cholangitis, they are related to bile infarcts extravasated bile in most cases and do not play an active role in duct destruction. The primary pattern of injury seen in primary sclerosing cholangitis is that of large duct obstruction, with bile ductular proliferation and overall mild portal inflammation. Onion skin periductal fibrosis and fibrous scars (fibro-obliterative duct lesions – see below) also indicate a diagnosis of primary sclerosing cholangitis.40 Liver biopsies in the setting of end-stage cirrhotic livers are more problematic, as both entities can show nonspecific features of chronic biliary disease, including ductopenia, cholate stasis, and copper accumulation.40
Prognosis and treatment
Prior to ursodeoxycholic acid, primary biliary cirrhosis was progressive in many patients. The 10 year survival
in asymptomatic patients varied from 50% to 70%, but dropped to 5 to 8 years once symptoms appeared.13 Ursodeoxycholic acid is an effective treatment and slows fibrosis and improves survival in the majority of patients.13 However, ursodeoxycholic acid is not curative, and patients must remain on treatment indefinitely.
in asymptomatic patients varied from 50% to 70%, but dropped to 5 to 8 years once symptoms appeared.13 Ursodeoxycholic acid is an effective treatment and slows fibrosis and improves survival in the majority of patients.13 However, ursodeoxycholic acid is not curative, and patients must remain on treatment indefinitely.
13.3 PRIMARY SCLEROSING CHOLANGITIS
Definition
Primary sclerosing cholangitis is a fibroinflammatory disease which targets the large and/or small bile ducts, resulting in destruction and stricture formation within the biliary tree.
Clinical features
There is geographic variability in the prevalence and incidence of primary sclerosing cholangitis, with higher rates in North America and Northern Europe and lower rates in Southern Europe and Asia.41, 42, 43, 44 North American and European incidence rates are estimated to be 1 per 100,000 persons.45 Primary sclerosing cholangitis preferentially affects men (M:F = 2:1), with a median age at diagnosis of approximately 40.45, 46, 47, 48
Approximately half of patients are asymptomatic at the time of diagnosis and are identified on routine workup or for an evaluation related to inflammatory bowel disease.25,42,44,49 Symptoms are typically vague and include fatigue or abdominal pain.42,47,50 Jaundice and fever are less common and suggest formation of a dominant stricture.44,51 Cholelithiasis is common, present in roughly one-fourth of gallbladders.52,53
Primary sclerosing cholangitis should be ruled out in any patient with a chronic, unexplained elevation in alkaline phosphatase, particularly in individuals with histories of inflammatory bowel disease.
The diagnostic criteria for primary sclerosing cholangitis include: (1) characteristic cholangiographic findings; (2) cholestatic biochemical profile; and (3) exclusion of secondary causes of sclerosing cholangitis.42,51 The main roles for liver biopsy are to evaluate for small duct primary sclerosing cholangitis (see below), rule out an overlap syndrome or superimposed process, and for fibrosis staging. A biopsy is not required to diagnose large duct primary sclerosing cholangitis.51,54
In the appropriate clinical setting, cholangiography is diagnostic in 95% of patients.42 The distribution of strictures varies somewhat by study, but involvement of both the intra- and extrahepatic biliary tree is most common, followed by isolated intrahepatic and isolated extrahepatic disease.47,51 One study demonstrated the following distribution of strictures in over 100 primary sclerosing cholangitis patients: intra- and extrahepatic ducts in 87%, isolated intrahepatic ducts in 11%, and isolated extrahepatic ducts in 2%.49
Laboratory findings
Though nonspecific, an elevated alkaline phosphatase level is present in the majority of patients.46,47,51,55 This and GGT elevations may be the only serum markers that are abnormal, and levels can fluctuate throughout the course of the disease.44 Transaminase levels are often normal, but may be elevated at 2 to 3× the upper limit of normal.44,51 As with primary biliary cirrhosis, if AST/ALT levels are greater than 5× upper limit, this raises the possibility of an autoimmune hepatitis overlap syndrome or other superimposed processes.51
At presentation, bilirubin levels are normal in the majority of patients and only become elevated in late stage disease, or in the setting of a dominant stricture.44,51
Unlike primary biliary cirrhosis, there is no diagnostic serologic test for primary sclerosing cholangitis. Patients may have a variety of nonspecific autoantibodies, with prevalence rates depending upon the population and study. According to one review of 19 studies, the median prevalence of perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) was 68%, with a range of 26% to 94%.56 ASMA and ANA are also variable, with median prevalence of 17% and 30%, respectively.56 Hypergammaglobulinemia is present in roughly 60% of patients.51 Elevated IgM levels are seen in 40% to 50% of cases.49 AMA is usually negative.24
Imaging
Cholangiography is the diagnostic test for large duct primary sclerosing cholangitis. Typical findings include a beaded pattern characterized by short, annular strictures which alternate with normal-to-dilated segments.49,51,57 Because endoscopic retrograde cholangiography is an invasive test with a complication rate of 10% (e.g., cholangitis and perforation), it has been supplanted by magnetic resonance cholangiography as the initial imaging modality.51,57 The latter is noninvasive and there is no radiation exposure.51 It has a sensitivity of >80% and specificity of >87%, providing accurate diagnoses in the majority of patients.51
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
