- Email: [email protected]
Primary Sclerosing Cholangitis
27 Primary Sclerosing Cholangitis Alberto Quaglia, MD, PhD, FRCPath
Incidence and Demographics 384 Clinical Manifestations 384 Laboratory Findings 384 Radiologic Features 384 Gross Pathology 384 Microscopic Pathology 385 Large Hilar/Parahilar Bile Ducts 385 Small Septal/Interlobular Bile Ducts 386 Small Peripheral Portal Tracts 387 Parenchymal Changes 387 Grading of Primary Sclerosing Cholangitis 387 Differential Diagnosis 387 Primary Biliary Cirrhosis 387 Autoimmune Hepatitis 387 IgG4-Related Sclerosing Cholangitis 389 Hepatolithiasis and Recurrent Pyogenic Cholangitis 389 Secondary Sclerosing Cholangitis 389 Other Chronic Liver Diseases 389 Dominant Stricture 389 Genetics 389 Treatment and Prognosis 389 Secondary (Acquired) Sclerosing Cholangitis 390 Abbreviations AIDS acquired immunodeficiency syndrome AIH autoimmune hepatitis ALP alkaline phosphatase ALT alanine aminotransferase AMA antimitochondrial antibody AST aspartate aminotransferase CK cytokeratin* *Although the prefix CK (for cytokeratin) is widely used in surgical pathology to designate human cytokeratins, a new consensus nomenclature published in 2006 (Schweizer J, Bowden PE, Coulombe PA, et al. New consensus nomenclature for mammalian keratins. ,%GNN$KQN 2006;174[2]:169–174) recommends the replacement of “cytokeratin” with “keratin” and the prefix “CK” with “K.”
ERCP GGT HLA IBD IgG IgM MDR3 MRCP pANCA pANNA PBC PSC SC-CIP SSC UDCA
endoscopic retrograde cholangiopancreatography gamma-glutamyl transferase human leukocyte antigen inflammatory bowel disease immunoglobulin G immunoglobulin M multidrug resistance P-glycoprotein 3 magnetic resonance cholangiopancreatography perinuclear antineutrophil cytoplasmic antibody perinuclear antineutrophil nuclear antibody primary biliary cirrhosis primary sclerosing cholangitis sclerosing cholangitis in critically ill patients secondary sclerosing cholangitis ursodeoxycholic acid
Primary sclerosing cholangitis (PSC) is a chronic inflammatory disorder of unknown etiology causing obliterative fibrosis and ectasia of the intrahepatic biliary tree, the extrahepatic biliary tree, or both. PSC typically involves large bile ducts, and cholangiographic findings of large duct damage form the mainstay of diagnosis. The term secondary or acquired is preferred for forms of sclerosing cholangitis that can be related to a cause such as ischemia, chronic biliary infection in patients with primary or acquired immunodeficiency, trauma, rupture of hydatid cyst, surgery, irradiation, Langerhans cell histiocytosis, tumors, or portal vein pathology. Exclusion of these causes is a requisite for the diagnosis of PSC.1 Small duct PSC is a variant that exclusively involves small bile ducts, 100 M or smaller in size, while sparing the large bile ducts. Small duct PSC lacks the characteristic cholangiographic findings of PSC. The diagnosis is made by the presence of typical microscopic features of PSC in small (i.e., septal and interlobular) bile ducts in a patient with chronic cholestatic liver disease. Small duct PSC accounts for approximately 5% of all cases of PSC.2,3 PSC is typically associated with other conditions. Up to 80% of patients with PSC have inflammatory bowel disease (IBD), predominantly ulcerative colitis.4 There is pancreatic involvement in a proportion of patients.5 PSC may overlap with autoimmune hepatitis (AIH).6,7 Conditions associated with sclerosing cholangitis in children are discussed in Chapter 8. 383
Practical Hepatic Pathology The clinical and laboratory features of PSC suggest an immunemediated disorder: These include the significant T-lymphocytic infiltrate around targeted bile ducts, presence of autoantibodies, and association with particular human leukocyte antigen (HLA) haplotypes and autoimmune diseases. However, when compared with typical autoimmune diseases, PSC is characterized by poor or no response to immunosuppression, male preponderance, and poor correlation of serum antibodies with clinical and laboratory parameters of the disease.
Incidence and Demographics PSC predominantly affects males.8 Although it can occur at any age, including infancy and childhood,9,10 it typically presents in the fourth to fifth decades of life. PSC is more common in Caucasians and northern Europeans than in southern Europeans, Asians, or Africans. The incidence is approximately 1 per 100,000 in northern Europe and the United States and less than 0.1 per 100,000 in southern Europe and Asia.11–13
Clinical Manifestations Symptoms of PSC include fatigue,14 jaundice, pruritus, and abdominal pain, and these may change over time with exacerbations and remissions15 of the disease. Patients may develop signs of infection because of superimposed bacterial cholangitis. Symptomatic patients usually have advanced disease. PSC has been reported to present with acute liver failure.16 PSC may be discovered during assessment or follow-up of patients with IBD, usually ulcerative colitis. IBD is usually diagnosed before PSC, but may even become apparent after liver transplantation.17 Also, PSC may be discovered or develop in patients treated for AIH. Other patients initially diagnosed with PSC may fulfill criteria for diagnosis of AIH.18 In addition, PSC may be discovered in patients with pancreatitis.19
Laboratory Findings Laboratory tests typically show increased levels of serum alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) more than those of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels.11 Serum ALP is increased three or more times above normal, although normal levels do not exclude PSC. Serum bilirubin levels may vary considerably. Serum immunoglobulin M (IgM) levels tend not to be raised. PSC is associated with autoantibodies, most frequently perinuclear antineutrophil cytoplasmic antibody (pANCA), and others, including antinuclear, anti–smooth muscle, and anticardiolipin antibodies, as well as rheumatoid factor.20 Although there has been great emphasis on the presence of pANCA in patients with PSC, these antibodies play a limited role in diagnosis, management, and prognosis of this disease. First, pANCA is not specific for PSC, the incidence being high in AIH and ulcerative colitis, among other diseases. Second, serum levels of pANCA do not correlate with clinical parameters or disease severity of PSC. The antibody persists after transplantation and after colectomy in patients with ulcerative colitis. It has been shown that the pattern of staining of pANCA is atypical and distinct from the classic staining pattern described in diseases such as microscopic polyangiitis; this probably reflects the fact that the antibody in PSC appears to target an antigen present on the nuclear envelope of neutrophils rather than a perinuclear cytoplasmic antigen. This antibody is therefore now referred to as peripheral antineutrophil nuclear antibody (pANNA).21,22
384
Radiologic Features Characteristic findings on endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP) include multifocal strictures giving rise to a typical “beading” appearance of large intrahepatic and extrahepatic bile ducts. As the disease advances and loss of ducts occurs, the biliary tree assumes a “pruned tree”–like appearance (Fig. 27-1). The latter appearance of the intrahepatic biliary tree may also occur in cirrhosis due to other causes. ERCP is the diagnostic mainstay, but it is invasive and carries definite risks such as pancreatitis. MRCP, on the other hand, is noninvasive,23 and its increasing use has led to advances in understanding of the disease and its associations with other conditions, particularly in children.24
Gross Pathology ERCP findings translate into the gross appearance of liver specimens removed at transplantation or examined at autopsy. Involvement of large bile ducts is evident as ectatic segments with or without bile sludge, calculi, or pus.25 Elsewhere, large bile ducts may be stenosed by scar tissue, and xanthoma-like patches may be present (Fig. 27-2). Scattered minute abscesses may also be evident in the more peripheral biliary tree. Areas of segmental or lobar parenchymal atrophy coupled with other areas of hypertrophy and expansion may lead to significant distortion of the anatomical shape of the liver (Figs. 27-3 and 27-4). This is probably a result of the combination of bile duct obstruction and phlebitis, with consequent vascular impairment, leading to parenchymal atrophy. The degree of fibrosis may vary from portal fibrosis to cirrhosis, alternating with areas of parenchymal collapse and regeneration. Broad areas of inflammation, xanthomatous change, and fibrosis may simulate tumoral masses, and these may be responsible for cases of “inflammatory pseudotumor” reported in the literature.26 Generous sampling of the biliary tree is advisable to exclude the presence of cholangiocarcinoma and to assess the biliary epithelium for dysplasia. Distinct areas of induration, in particular at the hilum, are suspect for malignancy. There is also an increased risk of gallbladder neoplasia.27
Figure 27-1. Magnetic resonance cholangiopancreatography shows biliary changes characteristic of primary sclerosing cholangitis, including “beading” of the large ducts and “pruning” of the peripheral branches. (Courtesy of Dr. John Karani, Department of Radiology, King’s College Hospital, London.)
Primary Sclerosing Cholangitis
27
* Figure 27-2. Slice of liver removed at transplantation for primary sclerosing cholangitis. The caudate lobe is hypertrophic (*). Bile ducts in the right and left lobe contain bile sludge. There are areas of parenchymal collapse. A xanthoma-like area of yellowish discoloration is present next to a dilated right lobe duct (CTTQY). A large ectatic duct in the left lobe is close to the capsular surface. Bar = 30 mm.
Microscopic Pathology PSC is characterized by inflammatory destruction of the biliary tree with concentric “onion skin” periductal fibrosis and eventual loss of biliary epithelium, with complete replacement of bile ducts by fibrous scars. Portal biliary fibrosis evolves into periportal and bridging fibrosis. The changes are uneven in distribution and chronology, and bile duct lesions at different stages of evolution coexist in different areas of the liver. Resection specimens allow examination of large hilar/parahilar bile ducts, whereas needle biopsy specimens usually include interlobular or septal bile ducts. In livers with advanced disease in which parenchymal atrophy may be extreme, large and ectatic bile ducts may be present close to the liver capsule and may be sampled at biopsy
Figure 27-3. Liver removed at transplantation for primary sclerosing cholangitis. Cirrhotic nodularity is evident. There is severe distortion of the lobar anatomy with atrophy of the left lobe and segments V and VIII, as well as hypertrophy of segments VI, VII, and the caudate lobe.
Figure 27-4. Transverse section of the liver shown in Figure 27-3. Note the areas of atrophy and segmental hyperplasia with effacement of the lobar anatomy. Bar = 30 mm.
(see Fig. 27-2). When PSC primarily involves small interlobular/septal bile ducts (small duct PSC), typical histologic features of PSC may be seen in needle biopsy specimens in the absence of cholangiographic evidence of disease.2,3
Large Hilar/Parahilar Bile Ducts These are surrounded by heavy infiltrates of neutrophils and eosinophils as well as lymphocytes and plasma cells. There is bile duct ulceration with bile extravasation and xanthogranuloma formation (Fig. 27-5). Granulomas with multinucleated giant cells are probably a reaction to extravasated bile.28 Bile ducts may be dilated and show an irregular outline and contain bile sludge or even well-formed stones (Fig. 27-6). The term onion skin refers to the presence of concentric periductal fibrosis, which may be observed in medium- and large-sized bile ducts (Figs. 27-7 and 27-8). Residual bile duct epithelium may show inflammatory atypia
Figure 27-5. Xanthoma formation. A cluster of foamy macrophages engulfing bile pigment is surrounded by a dense infiltrate of lymphocytes and plasma cells.
385
Practical Hepatic Pathology
*
Figure 27-6. A segmental bile duct shows extensive ulceration and contains a stone.
Figure 27-9. A subsegmental bile duct has been replaced by a cord of fibrous tissue (CTTQY). The accompanying artery and portal vein branches are evident nearby. The adjacent parenchyma (UVCT) has collapsed.
and metaplastic changes. Biliary epithelial dysplasia as well as in situ and invasive carcinoma may develop. Eventually, there is periductal or obliterative scar formation (Fig. 27-9). Peribiliary glands are often prominent, and when fibro-obliteration develops, their presence may indicate the site of a lost duct. Large areas of chronic inflammation and fibrosis may be present, particularly at the hilum, and they may simulate inflammatory myofibroblastic tumor (Fig. 27-10). There may be heavy infiltration of adjacent vascular structures (e.g., portal vein phlebitis). The combination of bile duct and vascular obstruction is probably responsible for the effacement of the lobar anatomy evident on gross examination, which manifests histologically as areas of parenchymal atrophy, extinction, fibrosis, and nodular regenerative hyperplasia.
Small Septal/Interlobular Bile Ducts
Figure 27-7. A septal bile duct is surrounded by an “onion skin”–like edematous concentric layer of fibrous stroma with admixed inflammatory cells.
Figure 27-8. Another example of “onion skin” periductal fibroinflammatory changes. 386
Needle biopsy samples may show changes secondary to cholangiodestruction and fibrosis of large ducts, direct involvement by the disease, or both. Direct involvement of small septal or interlobular bile ducts
Figure 27-10. Cellular fibrous stroma is permeated by lymphocytes and many plasma cells. Such areas may be extensive and may form well-defined masses. Inflammatory myofibroblastic (pseudo)tumor enters the differential diagnosis, particularly on biopsy specimens from such areas.
Primary Sclerosing Cholangitis inflammatory cell infiltrate and increased ductular profiles. Copperassociated protein may be demonstrated in periportal hepatocytes by orcein or Victoria blue stain (see Fig. 27-13B), sometimes in very small amount and focally. At later stages, biliary interface activity becomes more prominent, with florid ductular reaction and overt cholate stasis (Figs. 27-14 and 27-15).
27
Parenchymal Changes Cholate stasis consists of degenerative changes of hepatocytes at the limiting plate because of retention of bile salts. The changes include liver cell ballooning, Mallory hyaline formation, and more prominent accumulation of copper and copper-binding protein. With progression of the disease, portal-portal bridging fibrosis leads to cirrhotic transformation. Canalicular cholestasis is usually evident in end-stage livers. Its presence may indicate a dominant stricture, cholangiocarcinoma, or decompensation. Cholangiolar cholestasis may be seen in septic patients. Figure 27-11. An interlobular bile duct is directly involved by the inflammatory process. A bile duct of this size may be represented on a biopsy sample. The outline of the bile duct is irregular, and the epithelium is partly attenuated.
(Fig. 27-11) consists of cholangitis and/or pericholangitis, epithelial degenerative changes, attenuation and loss of bile duct epithelium, and periductal fibrosis (Fig. 27-12). “Onion skin” fibrosis may or may not be observed in fine needle biopsy specimens, because this change does not affect all ducts uniformly. Absence of “onion-skin” fibrosis in a fine needle biopsy specimen does not rule out PSC. On the other hand, it may be present in secondary sclerosing cholangitis (SSC) and should not be considered specific per se for a diagnosis of PSC. The late stage of the disease is characterized by fibrous scarring with disappearance of bile ducts, which are replaced by fibrous cords. Biliary remnants may be identified by immunohistochemistry for biliary cytokeratins (CK7, CK19, AE1/AE3).
Small Peripheral Portal Tracts Biopsy samples of peripheral liver often show changes secondary to injury of major bile ducts. Early indirect portal changes (Fig. 27-13) include mild portal fibrosis and edema, with a minimal mixed
Grading of Primary Sclerosing Cholangitis Four stages similar to those in primary biliary cirrhosis have been used to describe the evolution of PSC.29 At stage 1, changes are limited to portal tracts. At stage 2, there is involvement of the limiting plate with biliary interface activity. At stage 3, portal to portal fibrous linking occurs. At stage 4, there is cirrhosis.
Differential Diagnosis The diagnosis of PSC rests on close clinicopathologic correlation. The diagnostic criteria are similar in adults and children, but the differential diagnosis differs in these two age groups; the latter is discussed in Chapter 8. The differential diagnosis also depends on the stage of the disease. Subtle histologic changes suggestive of a cholangiopathy (see Fig. 27-13) may be seen at an early stage of the disease in liver biopsy specimens from patients with nonspecific abnormality of liver function tests or in patients suspected to be affected by other conditions. These changes are often dismissed as nonspecific, but they should raise the possibility of a cholangiopathy and warrant additional clinical investigations.
Primary Biliary Cirrhosis The pathologist may be asked to differentiate between PSC and primary biliary cirrhosis (PBC). On liver biopsy specimens, this distinction may be difficult and must rely on clinicopathologic correlation. PBC is more common in women and is associated with high levels of IgM and presence of antimitochondrial antibodies (AMAs), although cases of so-called “AMA-negative” PBC have been described. PBC is associated with autoimmune disorders such as sicca syndrome, thyroiditis, and arthritis. Cholangiography in PBC is often normal. Histologically, PBC is characterized by granulomatous cholangitis. The distinction between PBC and PSC is outlined in Table 26-4.
Autoimmune Hepatitis
Figure 27-12. With the increase of periductal fibrosis, the density of the peribiliary inflammation abates. Note the degenerative changes of the biliary epithelium.
The two conditions may overlap.30,31 Patients with an initial diagnosis of AIH may also show laboratory, cholangiographic, and/or histologic changes of a cholangiopathy.32,33 On the contrary, patients with an initial diagnosis of PSC may also fulfill criteria for AIH.18,34 One disease process may evolve into the other over time.35 The considerable zonal variation of the histologic changes in livers with PSC can be a source of confusion. In a patient with a clinical diagnosis of PSC, a biopsy sample from an area of parenchymal collapse 387
Practical Hepatic Pathology
A
B
C
D
Figure 27-13. Primary sclerosing cholangitis involving large hilar bile ducts. Liver biopsy samples of peripheral livers show indirect signs of the disease. (A) There is a slight ductular reaction with accompanying mild mixed inflammation. (B) Same portal tract as Figure 27-13A. Orcein stain shows focal dark-brown granules of copper-associated protein in periportal hepatocytes. (C) A small portal tract–like area shows a ductule and adjacent neutrophils. (D) Same case as Figure 27-13C. A different portal tract shows a more florid ductular reaction with an associated mild mixed inflammatory cell infiltrate.
Figure 27-14. Cholate stasis. Hepatocytes at the limiting plate show ballooning change and Mallory hyaline. There is ductular reaction in the adjacent stroma.
388
Figure 27-15. Cholate stasis: same field as in Figure 27-14. Orcein stain reveals abundant dark brown granules of copper-associated protein in hepatocytes at the limiting plate.
Primary Sclerosing Cholangitis or a patch of dense lymphoplasmacytic inflammation could raise the possibility of AIH. On the other hand, in a patient with clinically typical AIH, the presence of mild copper-associated protein deposition and ductular reaction could raise the possibility of a cholangiopathy. Once again, distinction relies on clinical, laboratory, serologic, and imaging findings. An autoimmune component is suggested by high titers of antinuclear and/or anti–smooth muscle antibodies, increased serum levels of immunoglobulin G (IgG), significantly elevated levels (3× normal) of AST and ALT, and, ultimately, clinical and laboratory response to immunosuppression. PSC, whether occurring by itself or in association with AIH, is diagnosed by significantly elevated (3× normal) biliary enzymes and cholangiographic findings. The overlap syndrome of PSC and AIH is discussed in Chapter 29.
IgG4-Related Sclerosing Cholangitis IgG4 is a subclass of IgG characterized by its low affinity for target antigen and inability to bind Clq. High serum IgG4 levels may be associated with atopic dermatitis, parasitic disease, and pemphigus.36 Patients with autoimmune or sclerosing pancreatitis have high IgG4 serum levels36 and many intrapancreatic and extrapancreatic IgG4-positive plasma cells by immunohistochemistry.37–41 The term IgG4-related systemic disease is now used to describe a syndrome characterized by increased serum IgG4 and multifocal IgG4positive sclerosing lymphoplasmacytic infiltrates responsive to steroid therapy.42,43 This disease typically involves the pancreas but can affect various other sites, including salivary glands, retroperitoneum, lymph nodes, kidneys, and the biliary tree.41,44 Involvement of the biliary tree (IgG4-related sclerosing cholangitis)44,45 manifests usually with obstructive jaundice and strictures of the intrapancreatic bile duct (51%) or the proximal extrahepatic/intrahepatic ducts (49%).42 Histologically, there is marked mural thickening of bile ducts by fibrosis and an associated dense lymphoplasmacytic infiltrate, with stenosis of the lumen. Obliterative phlebitis is characteristic. Immunohistochemistry shows many IgG4-positive plasma cells, even in peripheral portal tracts, which may be sampled by needle biopsy. Many eosinophils are present. The infiltrate involves peribiliary glands and nerves, but there is relative sparing of surface biliary epithelium. A review by Nakanuma and Zen provides a detailed description of IgG4 sclerosing cholangitis and the differential diagnosis with PSC.45 There is a tendency to develop inflammatory pseudotumor.45,46 IgG4-related sclerosing cholangitis responds to corticosteroids and recurs after withdrawal.
Hepatolithiasis and Recurrent Pyogenic Cholangitis These are typically diseases of the Far East but can be observed in Asian immigrants living in other countries. Hepatolithiasis is characterized by intrahepatic bilirubinate or cholesterol stone formation of uncertain cause. It can be complicated by superimposed bacterial infection and suppurative cholangitis. Recurrent pyogenic cholangitis is thought to be initiated by infestation with parasites such as Clonorchis sinensis, Opisthorchis viverrini, or Fasciola hepatica. Consequent cholangitis provokes biliary stone formation and superimposed bacterial infection with episodes of acute cholangitis.1 These two conditions overlap considerably and may show similarities to PSC. Of note, hepatolithiasis and suppurative cholangitis can be present in PSC.
Secondary Sclerosing Cholangitis PSC may be indistinguishable from secondary (acquired) sclerosing cholangitis (SSC) clinically, radiologically, and histologically. In adults, exclusion of secondary causes is requisite to establishing a diagnosis of
PSC; these include trauma, ischemia, surgery, chronic biliary infection in patients with primary or acquired immunodeficiency, rupture of hydatid cyst, irradiation, tumor, or portal vein pathology such as portal cavernoma with portal biliopathy.1 Of note, a previous history of biliary surgery or trauma does not rule out a preexistent clinically silent PSC. SSC is discussed further later in this chapter.
27
Other Chronic Liver Diseases Distortion of the biliary tree may occur in a range of acute and chronic liver diseases. A postmortem cholangiographic study of 154 livers of patients who did not have PSC showed that PSC-like cholangiographic changes were found frequently in cirrhosis, adult-type polycystic disease, submassive hepatic necrosis, metastatic carcinoma, and leukemia/ lymphoma infiltration.47
Dominant Stricture A minority of PSC patients (approximately 10% to 15%) develop a dominant stricture—a major obliteration at one point of the biliary tree with sudden worsening of jaundice. In these cases, the differential diagnosis is between an inflammatory stricture and cholangiocarcinoma. Tissue from dominant strictures may be obtained by fine needle biopsy or by bile duct brushing. The combination of biliary brushings and cancer antigen 19-9 may have diagnostic value.48 Special techniques may enhance the sensitivity of cytology for the diagnosis of cholangiocarcinoma.49
Genetics First-degree relatives of PSC patients have a 100-fold increased risk of developing the disease when compared with the general population.50 The inheritance pattern is complex, possibly because of the action of more than one gene.8 There is an association with HLA alleles,8,51–53 but other genes may be involved.11 In particular, the potential role of genes coding for hepatobiliary transporters is of interest. For example, patients with mutations of the ABCB4 gene encoding for the multidrug resistance P-glycoprotein 3 (MDR3) may develop cholangitis due to reduced formation of micelles and consequent detergent action of bile salts on biliary epithelium. The etiopathogenetic relationship of MDR3 mutations to PSC warrants further studies.54,55 An association between genetic variants of a natural killer cell receptor and its ligand and the risk of developing cholangiocarcinoma in PSC patients has been recently described.56,57
Treatment and Prognosis The clinical course is progressive with development of biliary cirrhosis. The median time from diagnosis to death or transplantation is reported to be 8 years.11 Disease progression occurs in the majority of patients who were asymptomatic at the time of diagnosis. Prognosis appears to be more favorable in patients with small duct disease.58–60 Prognostic models based on clinicopathologic parameters, including age, bilirubin level, histology, and presence of portal hypertension have been proposed.61–64 The severity of PSC does not correlate with the severity of the associated IBD, and treatment of one has little effect on the other.11 Complications include bacterial cholangitis, abscess formation, biliary duct stones, dominant stricture formation, and cholangiocarcinoma,65 as well as complications of IBD or other associated conditions. Ursodeoxycholic acid (UDCA) therapy can improve serum liver enzyme abnormalities, but the effect on symptoms, progression of fibrosis, and survival is controversial. Corticosteroids are of no use in patients with typical PSC but may be beneficial in patients who have an overlap syndrome with AIH. Dominant strictures are treated endoscopically.
389
Practical Hepatic Pathology The only potentially curative option is transplantation, but the disease is known to recur in the allograft. Cholangiocarcinoma can be discovered incidentally in a liver removed at transplantation, including in the gallbladder.27 The prevalence of cholangiocarcinoma in patients with PSC is between 7% and 13%.66 Patients with PSC at the cirrhotic stage are also at risk of developing hepatocellular carcinoma.67
Secondary (Acquired) Sclerosing Cholangitis SSC refers to cases of sclerosing cholangitis in which a possible etiologic factor can be recognized. A list of common causes is provided in Box 27-1. SSC has been shown to have poorer outcome than PSC.68 The biliary tree, unlike the liver, receives its blood supply entirely from the hepatic artery without a dual portal venous supply, making it susceptible to ischemia caused by hypotension or injury to the hepatic artery. In the liver allograft, ischemia is usually secondary to hepatic artery thrombosis or foamy cell arteriopathy as part of chronic rejection. The hepatic artery may appear patent radiologically.69 Superimposed bacterial or fungal infection with abscess formation may occur. Other causes of hepatic artery injury and SSC include ligation after abdominal trauma70 and intra-arterial infusion of floxuridine for the treatment of colorectal metastasis.71 A form of sclerosing cholangitis can occur in critically ill patients.72–74 Although severe trauma may have a direct effect, the pathogenesis is probably multifactorial, resulting from a combination of ischemia (e.g., arterial hypotension), superimposed infection by multiresistant bacteria,72 and bile cast formation. Infection of the biliary tree is the cause of SSC in patients with primary or secondary immunodeficiency. Ascending bacterial cholangitis, usually by gram-negative organisms, should be distinguished from the so-called “acquired immunodeficiency syndrome (AIDS) cholangiopathy.” The latter is seen in patients in advanced stages of AIDS, and its incidence is low where antiretroviral treatment is available.1 There may be intrahepatic or extrahepatic biliary involvement, gallbladder disease, and/or stenosis of the papilla of Vater. Histologic examination of the biliary tree may identify various organisms, sometimes in combination; the most frequent are cytomegalovirus and cryptosporidia (Cryptosporidium parvum), and occasionally microsporidia are found.75–77 C. parvum is considered to be the primary cause of AIDS cholangiopathy.78,79 Organisms are more easily seen in association with extrahepatic biliary tree epithelium, although cryptosporidia can be identified in interlobular bile ducts on liver biopsy. Cryptosporidium cholangiopathy has also been described in a renal transplant patient.80
Box 27-1. Secondary Causes of Sclerosing Cholangitis Ischemia Sclerosing cholangitis in critically ill patients (SC-CIP) Transarterial chemotherapy Arterial pathology in allograft Infection/infestation: primary/secondary immunodeficiency Cryptosporidium Cytomegalovirus Microsporidium Tumor Langerhans cell histiocytosis Systemic mastocytosis Other malignant tumors Other Mechanical obstruction by choledochal varices Trauma Radiation injury Hydatid (rupture, postinjection)
390
As many as 60% of children with primary immunodeficiency have sclerosing cholangitis.81 Children with primary immunodeficiency, in particular hyperIgM syndrome, develop cholangitis as well as acalculous cholecystitis,82 which is usually caused by cryptosporidium83 and sometimes by other microorganisms.84 This form of SSC may resolve after bone marrow transplantation85 but recurs after liver transplantation.86 Rupture of hydatid cysts, in particular after scolicidal injection, can result in a form of chemical SSC.87–89 In patients with portal vein obstruction, bypass venous collaterals (portal cavernoma) can compress the biliary tree,90,91 resulting in a form of SSC; intrahepatic lithiasis also occurs in this condition. SSC due to Langerhans cell histiocytosis has been observed in children92–94 and in adults.92,95 Patients with systemic mastocytosis have developed SSC.96,97 Radiation therapy for biliary or extrabiliary malignancy may result in biliary stricture formation.98–102 Suggested Readings Abdalian R, Heathcote EJ. Sclerosing cholangitis: a focus on secondary causes. Hepatology. 2006;44:1063–1074. Karlsen TH, Schrumpf E, Boberg KM. Genetic epidemiology of primary sclerosing cholangitis. World J Gastroenterol. 2007;13:5421–5431. LaRusso NF, Shneider BL, Black D, et al. Primary sclerosing cholangitis: summary of a workshop. Hepatology. 2006;44:746–764. Nakanuma Y, Zen Y. Pathology and immunopathology of immunoglobulin G4-related sclerosing cholangitis: the latest addition to the sclerosing cholangitis family. Hepatol Res. 2007;37(suppl 3):S478–S486. Portmann B, Nakanuma Y. Diseases of the bile ducts. In: MacSween RNM, Burt AD, Portmann B, et al, eds. MacSween’s Pathology of the Liver. 5th ed. London: Churchill Livingstone/Elsevier; 2007:973 x.
References 1. Abdalian R, Heathcote EJ. Sclerosing cholangitis: a focus on secondary causes. Hepatology. 2006;44:1063–1074. 2. Ludwig J. Small-duct primary sclerosing cholangitis. Semin Liver Dis. 1991;11:11–17. 3. Nikolaidis NL, Giouleme OI, Tziomalos KA, et al. Small-duct primary sclerosing cholangitis. A single-center seven-year experience. Dig Dis Sci. 2005;50:324–326. 4. Broome U, Bergquist A. Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer. Semin Liver Dis. 2006;26:31–41. 5. Takikawa H, Takamori Y, Tanaka A, et al. Analysis of 388 cases of primary sclerosing cholangitis in Japan: presence of a subgroup without pancreatic involvement in older patients. Hepatol Res. 2004;29:153–159. 6. Okazaki K. Is primary sclerosing cholangitis different from sclerosing cholangitis with autoimmune pancreatitis? J Gastroenterol. 2007;42:600–601. 7. Okazaki K, Uchida K, Matsushita M, et al. Autoimmune pancreatitis. Intern Med. 2005; 44:1215–1223. 8. Karlsen TH, Schrumpf E, Boberg KM. Genetic epidemiology of primary sclerosing cholangitis. World J Gastroenterol. 2007;13:5421–5431. 9. el Shabrawi M, Wilkinson ML, Portmann B, et al. Primary sclerosing cholangitis in childhood. Gastroenterology. 1987;92:1226–1235. 10. Feldstein AE, Perrault J, El Youssif M, et al. Primary sclerosing cholangitis in children: a long-term follow-up study. Hepatology. 2003;38:210–217. 11. LaRusso NF, Shneider BL, Black D, et al. Primary sclerosing cholangitis: summary of a workshop. Hepatology. 2006;44:746–764. 12. Lazaridis KN. Sclerosing cholangitis epidemiology and etiology. J Gastrointest Surg. 2008; 12:417–419. 13. Levy C, Lindor KD. Primary sclerosing cholangitis: Epidemiology, natural history, and prognosis. Semin Liver Dis. 2006;26:22–30. 14. Bjornsson E, Simren M, Olsson R, et al. Fatigue in patients with primary sclerosing cholangitis. Scand J Gastroenterol. 2004;39:961–968. 15. Steele IL, Levy C, Lindor KD. Primary sclerosing cholangitis—approach to diagnosis. Med Gen Med. 2007;9:20. 16. Bergquist A, Glaumann H, Lindberg B, et al. Primary sclerosing cholangitis can present with acute liver failure: report of two cases. J Hepatol. 2006;44:1005–1008. 17. Papatheodoridis GV, Hamilton M, Mistry PK, et al. Ulcerative colitis has an aggressive course after orthotopic liver transplantation for primary sclerosing cholangitis. Gut. 1998;43:639–644. 18. Mieli-Vergani G, Vergani D. Sclerosing cholangitis in the paediatric patient. Best Pract Res Clin Gastroenterol. 2001;15:681–690. 19. Kawaguchi K, Koike M, Tsuruta K, et al. Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas. Hum Pathol. 1991;22:387–395.
Primary Sclerosing Cholangitis 20. Angulo P, Peter JB, Gershwin ME, et al. Serum autoantibodies in patients with primary sclerosing cholangitis. J Hepatol. 2000;32:182–187. 21. Chapman R, Cullen S. Etiopathogenesis of primary sclerosing cholangitis. World J Gastroenterol. 2008;14:3350–3359. 22. Terjung B, Spengler U, Sauerbruch T, et al. “Atypical p-ANCA” in IBD and hepatobiliary disorders react with a 50-kilodalton nuclear envelope protein of neutrophils and myeloid cell lines. Gastroenterology. 2000;119:310–322. 23. Lindor KD. Characteristics of primary sclerosing cholangitis in the USA. Hepatol Res. 2007;37(suppl 3):S474–S477. 24. Tipnis NA, Werlin SL. The use of magnetic resonance cholangiopancreatography in children. Curr Gastroenterol Rep. 2007;9:225–229. 25. Kaw M, Silverman WB, Rabinovitz M, et al. Biliary tract calculi in primary sclerosing cholangitis. Am J Gastroenterol. 1995;90:72–75. 26. Toda K, Yasuda I, Nishigaki Y, et al. Inflammatory pseudotumor of the liver with primary sclerosing cholangitis. J Gastroenterol. 2000;35:304–309. 27. Lewis JT, Talwalkar JA, Rosen CB, et al. Prevalence and risk factors for gallbladder neoplasia in patients with primary sclerosing cholangitis: evidence for a metaplasia-dysplasia-carcinoma sequence. Am J Surg Pathol. 2007;31:907–913. 28. Ludwig J, Colina F, Poterucha JJ. Granulomas in primary sclerosing cholangitis. Liver. 1995;15:307–312. 29. Ludwig J, La Russo NF, Wiesner RH, et al. Primary sclerosing cholangitis. In: Peters R, Craig JR, eds. Liver Pathology: Contemporary Issues in Surgical Pathology. New York: Churchill Livingstone; 1986:193–213. 30. Gohlke F, Lohse AW, Dienes HP, et al. Evidence for an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis. J Hepatol. 1996;24:699–705. 31. McNair AN, Moloney M, Portmann BC, et al. Autoimmune hepatitis overlapping with primary sclerosing cholangitis in five cases. Am J Gastroenterol. 1998;93:777–784. 32. Gregorio GV, Portmann B, Karani J, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology. 2001;33:544–553. 33. Abdalian R, Dhar P, Jhaveri K, et al. Prevalence of sclerosing cholangitis in adults with autoimmune hepatitis: evaluating the role of routine magnetic resonance imaging. Hepatology. 2008;47:949–957. 34. Boberg KM, Fausa O, Haaland T, et al. Features of autoimmune hepatitis in primary sclerosing cholangitis: an evaluation of 114 primary sclerosing cholangitis patients according to a scoring system for the diagnosis of autoimmune hepatitis. Hepatology. 1996;23:1369–1376. 35. Abdo AA, Bain VG, Kichian K, et al. Evolution of autoimmune hepatitis to primary sclerosing cholangitis: a sequential syndrome. Hepatology. 2002;36:1393–1399. 36. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732–738. 37. Kamisawa T. IgG4-positive plasma cells specifically infiltrate various organs in autoimmune pancreatitis. Pancreas. 2004;29:167–168. 38. Kamisawa T, Egawa N, Nakajima H. Autoimmune pancreatitis is a systemic autoimmune disease. Am J Gastroenterol. 2003;98:2811–2812. 39. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38:982–984. 40. Kamisawa T, Funata N, Hayashi Y, et al. Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Gut. 2003;52:683–687. 41. Kamisawa T, Nakajima H, Egawa N, et al. IgG4-related sclerosing disease incorporating sclerosing pancreatitis, cholangitis, sialadenitis and retroperitoneal fibrosis with lymphadenopathy. Pancreatology. 2006;6:132–137. 42. Ghazale A, Chari ST, Zhang L, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology. 2008;134:706–715. 43. Masaki Y, Dong L, Kurose N, et al. Proposal for a new clinical entity, IgG4-positive multi-organ lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis. 2008; Epub. 44. Zen Y, Harada K, Sasaki M, et al. IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis? Am J Surg Pathol. 2004;28:1193–1203. 45. Nakanuma Y, Zen Y. Pathology and immunopathology of immunoglobulin G4-related sclerosing cholangitis: the latest addition to the sclerosing cholangitis family. Hepatol Res. 2007;37(suppl 3):S478–S486. 46. Toosi MN, Heathcote J. Pancreatic pseudotumor with sclerosing pancreato-cholangitis: is this a systemic disease? Am J Gastroenterol. 2004;99:377–382. 47. Terada T, Nakanuma Y. Intrahepatic cholangiographic appearance simulating primary sclerosing cholangitis in several hepatobiliary diseases: a postmortem cholangiographic and histopathological study in 154 livers at autopsy. Hepatology. 1995;22:75–81. 48. Furmanczyk PS, Grieco VS, Agoff SN. Biliary brush cytology and the detection of cholangiocarcinoma in primary sclerosing cholangitis: evaluation of specific cytomorphologic features and CA19-9 levels. Am J Clin Pathol. 2005;124:355–360. 49. Moreno Luna LE, Kipp B, Halling KC, et al. Advanced cytologic techniques for the detection of malignant pancreatobiliary strictures. Gastroenterology. 2006;131:1064–1072. 50. Bergquist A, Lindberg G, Saarinen S, et al. Increased prevalence of primary sclerosing cholangitis among first-degree relatives. J Hepatol. 2005;42:252–256. 51. Donaldson PT, Farrant JM, Wilkinson ML, et al. Dual association of HLA DR2 and DR3 with primary sclerosing cholangitis. Hepatology. 1991;13:129–133.
52. Donaldson PT, Norris S. Evaluation of the role of MHC class II alleles, haplotypes and selected amino acid sequences in primary sclerosing cholangitis. Autoimmunity. 2002;35:555–564. 53. Neri TM, Cavestro GM, Seghini P, et al. Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population. Dig Liver Dis. 2003;35:571–576. 54. Trauner M, Fickert P, Wagner M. MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. Semin Liver Dis. 2007;27:77–98. 55. Pauli-Magnus C, Kerb R, Fattinger K, et al. BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology. 2004; 39:779–791. 56. Melum E, Karlsen TH, Schrumpf E, et al. Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms. Hepatology. 2008;47:90–96. 57. Lazaridis KN. Dissecting the genetic susceptibility for cholangiocarcinoma in primary sclerosing cholangitis. Hepatology. 2008;47:8–10. 58. Bjornsson E, Boberg KM, Cullen S, et al. Patients with small duct primary sclerosing cholangitis have a favorable long term prognosis. Gut. 2002;51:731–735. 59. Angulo P, Maor-Kendler Y, Lindor KD. Small-duct primary sclerosing cholangitis: a long-term follow-up study. Hepatology. 2002;35:1494–1500. 60. Broome U, Glaumann H, Lindstom E, et al. Natural history and outcome in 32 Swedish patients with small duct primary sclerosing cholangitis (PSC). J Hepatol. 2002;36:586–589. 61. Broome U, Olsson R, Loof L, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut. 1996;38:610–615. 62. Farrant JM, Hayllar KM, Wilkinson ML, et al. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology. 1991;100:1710–1717. 63. Kim WR, Therneau TM, Wiesner RH, et al. A revised natural history model for primary sclerosing cholangitis. Mayo Clin Proc. 2000;75:688–694. 64. Neuberger J, Gunson B, Komolmit P, et al. Pretransplant prediction of prognosis after liver transplantation in primary sclerosing cholangitis using a Cox regression model. Hepatology. 1999;29:1375–1379. 65. Burak K, Angulo P, Pasha TM, et al. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2004;99:523–526. 66. Lazaridis KN, Gores GJ. Primary sclerosing cholangitis and cholangiocarcinoma. Semin Liver Dis. 2006;26:42–51. 67. Harnois DM, Gores GJ, Ludwig J, et al. Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer? J Hepatol. 1997;27:512–516. 68. Gossard AA, Angulo P, Lindor KD. Secondary sclerosing cholangitis: a comparison to primary sclerosing cholangitis. Am J Gastroenterol. 2005;100:1330–1333. 69. Buis CI, Hoekstra H, Verdonk RC, et al. Causes and consequences of ischemic-type biliary lesions after liver transplantation. J Hepatobiliary Pancreat Surg. 2006;13:517–524. 70. Martin de Carpi M, Tarrado X, Varea V. Sclerosing cholangitis secondary to hepatic artery ligation after abdominal trauma. Eur J Gastroenterol Hepatol. 2005;17:987–990. 71. Barnett KT, Malafa MP. Complications of hepatic artery infusion: a review of 4580 reported cases. Int J Gastrointest Cancer. 2001;30:147–160. 72. Gelbmann CM, Rummele P, Wimmer M, et al. Ischemic-like cholangiopathy with secondary sclerosing cholangitis in critically ill patients. Am J Gastroenterol. 2007;102:1221–1229. 73. Jaeger C, Mayer G, Henrich R, et al. Secondary sclerosing cholangitis after long-term treatment in an intensive care unit: clinical presentation, endoscopic findings, treatment, and follow-up. Endoscopy. 2006;38:730–734. 74. Benninger J, Grobholz R, Oeztuerk Y, et al. Sclerosing cholangitis following severe trauma: description of a remarkable disease entity with emphasis on possible pathophysiologic mechanisms. World J Gastroenterol. 2005;11:4199–4205. 75. Sheikh RA, Prindiville TP, Yenamandra S, et al. Microsporidial AIDS cholangiopathy due to Encephalitozoon intestinalis: case report and review. Am J Gastroenterol. 2000; 95:2364–2371. 76. Liberman E, Yen TS. Foamy macrophages in acquired immunodeficiency syndrome cholangiopathy with 'PEGRJCNKVQ\QQPKPVGUVKPCNKU. Arch Pathol Lab Med. 1997;121:985–988. 77. Willson R, Harrington R, Stewart B, et al. Human immunodeficiency virus 1-associated necrotizing cholangitis caused by infection with 5GRVCVC KPVGUVKPCNKU. Gastroenterology. 1995;108:247–251. 78. Chen XM, LaRusso NF. Cryptosporidiosis and the pathogenesis of AIDS-cholangiopathy. Semin Liver Dis. 2002;22:277–289. 79. Alpini G, McGill JM, LaRusso NF. The pathobiology of biliary epithelia. Hepatology. 2002;35:1256–1268. 80. Abdo A, Klassen J, Urbanski S, et al. Reversible sclerosing cholangitis secondary to cryptosporidiosis in a renal transplant patient. J Hepatol. 2003;38:688–691. 81. Rodrigues F, Davies EG, Harrison P, et al. Liver disease in children with primary immunodeficiencies. J Pediatr. 2004;145:333–339. 82. Lin SC, Shyur SD, Ma YC, et al. Recurrent acalculous cholecystitis and sclerosing cholangitis in a patient with X-linked hyper-immunoglobulin M syndrome. J Formos Med Assoc. 2005;104:421–426. 83. Winkelstein JA, Marino MC, Ochs H, et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore). 2003;82:373–384. 84. Bhatia V, Garg PK, Agarwal V, et al. Inflammatory papillary stenosis due to )KCTFKCNCODNKC in a patient with hyper-immunoglobulin M immunodeficiency syndrome. Gastrointest Endosc. 2007;66:181–182.
27
391
Practical Hepatic Pathology 85. Dimicoli S, Bensoussan D, Latger-Cannard V, et al. Complete recovery from %T[RVQURQTKFKWO RCTXWO infection with gastroenteritis and sclerosing cholangitis after successful bone marrow transplantation in two brothers with X-linked hyper-IgM syndrome. Bone Marrow Transplant. 2003;32:733–737. 86. Levy J, Espanol-Boren T, Thomas C, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr. 1997;131:47–54. 87. Tsimoyiannis EC, Grantzis E, Moutesidou K, et al. Secondary sclerosing cholangitis: after injection of formaldehyde into hydatid cysts in the liver. Eur J Surg. 1995;161:299–300. 88. Taranto D, Beneduce F, Vitale LM, et al. Chemical sclerosing cholangitis after injection of scolicidal solution. Ital J Gastroenterol. 1995;27:78–79. 89. Castellano G, Moreno-Sanchez D, Gutierrez J, et al. Caustic sclerosing cholangitis. Report of four cases and a cumulative review of the literature. Hepatogastroenterology. 1994;41:458–470. 90. Khuroo MS, Yattoo GN, Zargar SA, et al. Biliary abnormalities associated with extrahepatic portal venous obstruction. Hepatology. 1993;17:807–813. 91. Dilawari JB, Chawla YK. Pseudosclerosing cholangitis in extrahepatic portal venous obstruction. Gut. 1992;33:272–276. 92. Jaffe R. Liver involvement in the histiocytic disorders of childhood. Pediatr Dev Pathol. 2004;7:214–225. 93. Braier J, Ciocca M, Latella A, et al. Cholestasis, sclerosing cholangitis, and liver transplantation in Langerhans cell histiocytosis. Med Pediatr Oncol. 2002;38:178–182.
392
94. Zandi P, Panis Y, Debray D, et al. Pediatric liver transplantation for Langerhans’ cell histiocytosis. Hepatology. 1995;21:129–133. 95. Griffiths W, Davies S, Gibbs P, et al. Liver transplantation in an adult with sclerosing cholangitis due to Langerhans cell histiocytosis. J Hepatol. 2006;44:829–831. 96. Baron TH, Koehler RE, Rodgers WH, et al. Mast cell cholangiopathy: another cause of sclerosing cholangitis. Gastroenterology. 1995;109:1677–1681. 97. Marbello L, Anghilieri M, Nosari A, et al. Aggressive systemic mastocytosis mimicking sclerosing cholangitis. Haematologica. 2004;89:ECR35. 98. Di Fiore F, Savoye-Collet C, Savoye G, et al. Magnetic resonance cholangiographic assessment of a delayed radiation-induced bile duct stricture. Dig Liver Dis. 2001;33:584–586. 99. Nakakubo Y, Kondo S, Katoh H, et al. Biliary stricture as a possible late complication of radiation therapy. Hepatogastroenterology. 2000;47:1531–1532. 100. Cherqui D, Palazzo L, Piedbois P, et al. Common bile duct stricture as a late complication of upper abdominal radiotherapy. J Hepatol. 1994;20:693–697. 101. Halevy A, Adam A, Stamp G, et al. Radiation stricture of the biliary ducts: an emerging new entity? HPB Surg. 1992;5:267–270. 102. Martenson Jr JA, Gunderson LL, Buskirk SJ, et al. Hepatic duct stricture after radical radiation therapy for biliary cancer: recurrence or fibrosis? Mayo Clin Proc. 1986;61:530–536.
Incidence and Demographics 384 Clinical Manifestations 384 Laboratory Findings 384 Radiologic Features 384 Gross Pathology 384 Microscopic Pathology 385 Large Hilar/Parahilar Bile Ducts 385 Small Septal/Interlobular Bile Ducts 386 Small Peripheral Portal Tracts 387 Parenchymal Changes 387 Grading of Primary Sclerosing Cholangitis 387 Differential Diagnosis 387 Primary Biliary Cirrhosis 387 Autoimmune Hepatitis 387 IgG4-Related Sclerosing Cholangitis 389 Hepatolithiasis and Recurrent Pyogenic Cholangitis 389 Secondary Sclerosing Cholangitis 389 Other Chronic Liver Diseases 389 Dominant Stricture 389 Genetics 389 Treatment and Prognosis 389 Secondary (Acquired) Sclerosing Cholangitis 390 Abbreviations AIDS acquired immunodeficiency syndrome AIH autoimmune hepatitis ALP alkaline phosphatase ALT alanine aminotransferase AMA antimitochondrial antibody AST aspartate aminotransferase CK cytokeratin* *Although the prefix CK (for cytokeratin) is widely used in surgical pathology to designate human cytokeratins, a new consensus nomenclature published in 2006 (Schweizer J, Bowden PE, Coulombe PA, et al. New consensus nomenclature for mammalian keratins. ,%GNN$KQN 2006;174[2]:169–174) recommends the replacement of “cytokeratin” with “keratin” and the prefix “CK” with “K.”
ERCP GGT HLA IBD IgG IgM MDR3 MRCP pANCA pANNA PBC PSC SC-CIP SSC UDCA
endoscopic retrograde cholangiopancreatography gamma-glutamyl transferase human leukocyte antigen inflammatory bowel disease immunoglobulin G immunoglobulin M multidrug resistance P-glycoprotein 3 magnetic resonance cholangiopancreatography perinuclear antineutrophil cytoplasmic antibody perinuclear antineutrophil nuclear antibody primary biliary cirrhosis primary sclerosing cholangitis sclerosing cholangitis in critically ill patients secondary sclerosing cholangitis ursodeoxycholic acid
Primary sclerosing cholangitis (PSC) is a chronic inflammatory disorder of unknown etiology causing obliterative fibrosis and ectasia of the intrahepatic biliary tree, the extrahepatic biliary tree, or both. PSC typically involves large bile ducts, and cholangiographic findings of large duct damage form the mainstay of diagnosis. The term secondary or acquired is preferred for forms of sclerosing cholangitis that can be related to a cause such as ischemia, chronic biliary infection in patients with primary or acquired immunodeficiency, trauma, rupture of hydatid cyst, surgery, irradiation, Langerhans cell histiocytosis, tumors, or portal vein pathology. Exclusion of these causes is a requisite for the diagnosis of PSC.1 Small duct PSC is a variant that exclusively involves small bile ducts, 100 M or smaller in size, while sparing the large bile ducts. Small duct PSC lacks the characteristic cholangiographic findings of PSC. The diagnosis is made by the presence of typical microscopic features of PSC in small (i.e., septal and interlobular) bile ducts in a patient with chronic cholestatic liver disease. Small duct PSC accounts for approximately 5% of all cases of PSC.2,3 PSC is typically associated with other conditions. Up to 80% of patients with PSC have inflammatory bowel disease (IBD), predominantly ulcerative colitis.4 There is pancreatic involvement in a proportion of patients.5 PSC may overlap with autoimmune hepatitis (AIH).6,7 Conditions associated with sclerosing cholangitis in children are discussed in Chapter 8. 383
Practical Hepatic Pathology The clinical and laboratory features of PSC suggest an immunemediated disorder: These include the significant T-lymphocytic infiltrate around targeted bile ducts, presence of autoantibodies, and association with particular human leukocyte antigen (HLA) haplotypes and autoimmune diseases. However, when compared with typical autoimmune diseases, PSC is characterized by poor or no response to immunosuppression, male preponderance, and poor correlation of serum antibodies with clinical and laboratory parameters of the disease.
Incidence and Demographics PSC predominantly affects males.8 Although it can occur at any age, including infancy and childhood,9,10 it typically presents in the fourth to fifth decades of life. PSC is more common in Caucasians and northern Europeans than in southern Europeans, Asians, or Africans. The incidence is approximately 1 per 100,000 in northern Europe and the United States and less than 0.1 per 100,000 in southern Europe and Asia.11–13
Clinical Manifestations Symptoms of PSC include fatigue,14 jaundice, pruritus, and abdominal pain, and these may change over time with exacerbations and remissions15 of the disease. Patients may develop signs of infection because of superimposed bacterial cholangitis. Symptomatic patients usually have advanced disease. PSC has been reported to present with acute liver failure.16 PSC may be discovered during assessment or follow-up of patients with IBD, usually ulcerative colitis. IBD is usually diagnosed before PSC, but may even become apparent after liver transplantation.17 Also, PSC may be discovered or develop in patients treated for AIH. Other patients initially diagnosed with PSC may fulfill criteria for diagnosis of AIH.18 In addition, PSC may be discovered in patients with pancreatitis.19
Laboratory Findings Laboratory tests typically show increased levels of serum alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) more than those of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels.11 Serum ALP is increased three or more times above normal, although normal levels do not exclude PSC. Serum bilirubin levels may vary considerably. Serum immunoglobulin M (IgM) levels tend not to be raised. PSC is associated with autoantibodies, most frequently perinuclear antineutrophil cytoplasmic antibody (pANCA), and others, including antinuclear, anti–smooth muscle, and anticardiolipin antibodies, as well as rheumatoid factor.20 Although there has been great emphasis on the presence of pANCA in patients with PSC, these antibodies play a limited role in diagnosis, management, and prognosis of this disease. First, pANCA is not specific for PSC, the incidence being high in AIH and ulcerative colitis, among other diseases. Second, serum levels of pANCA do not correlate with clinical parameters or disease severity of PSC. The antibody persists after transplantation and after colectomy in patients with ulcerative colitis. It has been shown that the pattern of staining of pANCA is atypical and distinct from the classic staining pattern described in diseases such as microscopic polyangiitis; this probably reflects the fact that the antibody in PSC appears to target an antigen present on the nuclear envelope of neutrophils rather than a perinuclear cytoplasmic antigen. This antibody is therefore now referred to as peripheral antineutrophil nuclear antibody (pANNA).21,22
384
Radiologic Features Characteristic findings on endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP) include multifocal strictures giving rise to a typical “beading” appearance of large intrahepatic and extrahepatic bile ducts. As the disease advances and loss of ducts occurs, the biliary tree assumes a “pruned tree”–like appearance (Fig. 27-1). The latter appearance of the intrahepatic biliary tree may also occur in cirrhosis due to other causes. ERCP is the diagnostic mainstay, but it is invasive and carries definite risks such as pancreatitis. MRCP, on the other hand, is noninvasive,23 and its increasing use has led to advances in understanding of the disease and its associations with other conditions, particularly in children.24
Gross Pathology ERCP findings translate into the gross appearance of liver specimens removed at transplantation or examined at autopsy. Involvement of large bile ducts is evident as ectatic segments with or without bile sludge, calculi, or pus.25 Elsewhere, large bile ducts may be stenosed by scar tissue, and xanthoma-like patches may be present (Fig. 27-2). Scattered minute abscesses may also be evident in the more peripheral biliary tree. Areas of segmental or lobar parenchymal atrophy coupled with other areas of hypertrophy and expansion may lead to significant distortion of the anatomical shape of the liver (Figs. 27-3 and 27-4). This is probably a result of the combination of bile duct obstruction and phlebitis, with consequent vascular impairment, leading to parenchymal atrophy. The degree of fibrosis may vary from portal fibrosis to cirrhosis, alternating with areas of parenchymal collapse and regeneration. Broad areas of inflammation, xanthomatous change, and fibrosis may simulate tumoral masses, and these may be responsible for cases of “inflammatory pseudotumor” reported in the literature.26 Generous sampling of the biliary tree is advisable to exclude the presence of cholangiocarcinoma and to assess the biliary epithelium for dysplasia. Distinct areas of induration, in particular at the hilum, are suspect for malignancy. There is also an increased risk of gallbladder neoplasia.27
Figure 27-1. Magnetic resonance cholangiopancreatography shows biliary changes characteristic of primary sclerosing cholangitis, including “beading” of the large ducts and “pruning” of the peripheral branches. (Courtesy of Dr. John Karani, Department of Radiology, King’s College Hospital, London.)
Primary Sclerosing Cholangitis
27
* Figure 27-2. Slice of liver removed at transplantation for primary sclerosing cholangitis. The caudate lobe is hypertrophic (*). Bile ducts in the right and left lobe contain bile sludge. There are areas of parenchymal collapse. A xanthoma-like area of yellowish discoloration is present next to a dilated right lobe duct (CTTQY). A large ectatic duct in the left lobe is close to the capsular surface. Bar = 30 mm.
Microscopic Pathology PSC is characterized by inflammatory destruction of the biliary tree with concentric “onion skin” periductal fibrosis and eventual loss of biliary epithelium, with complete replacement of bile ducts by fibrous scars. Portal biliary fibrosis evolves into periportal and bridging fibrosis. The changes are uneven in distribution and chronology, and bile duct lesions at different stages of evolution coexist in different areas of the liver. Resection specimens allow examination of large hilar/parahilar bile ducts, whereas needle biopsy specimens usually include interlobular or septal bile ducts. In livers with advanced disease in which parenchymal atrophy may be extreme, large and ectatic bile ducts may be present close to the liver capsule and may be sampled at biopsy
Figure 27-3. Liver removed at transplantation for primary sclerosing cholangitis. Cirrhotic nodularity is evident. There is severe distortion of the lobar anatomy with atrophy of the left lobe and segments V and VIII, as well as hypertrophy of segments VI, VII, and the caudate lobe.
Figure 27-4. Transverse section of the liver shown in Figure 27-3. Note the areas of atrophy and segmental hyperplasia with effacement of the lobar anatomy. Bar = 30 mm.
(see Fig. 27-2). When PSC primarily involves small interlobular/septal bile ducts (small duct PSC), typical histologic features of PSC may be seen in needle biopsy specimens in the absence of cholangiographic evidence of disease.2,3
Large Hilar/Parahilar Bile Ducts These are surrounded by heavy infiltrates of neutrophils and eosinophils as well as lymphocytes and plasma cells. There is bile duct ulceration with bile extravasation and xanthogranuloma formation (Fig. 27-5). Granulomas with multinucleated giant cells are probably a reaction to extravasated bile.28 Bile ducts may be dilated and show an irregular outline and contain bile sludge or even well-formed stones (Fig. 27-6). The term onion skin refers to the presence of concentric periductal fibrosis, which may be observed in medium- and large-sized bile ducts (Figs. 27-7 and 27-8). Residual bile duct epithelium may show inflammatory atypia
Figure 27-5. Xanthoma formation. A cluster of foamy macrophages engulfing bile pigment is surrounded by a dense infiltrate of lymphocytes and plasma cells.
385
Practical Hepatic Pathology
*
Figure 27-6. A segmental bile duct shows extensive ulceration and contains a stone.
Figure 27-9. A subsegmental bile duct has been replaced by a cord of fibrous tissue (CTTQY). The accompanying artery and portal vein branches are evident nearby. The adjacent parenchyma (UVCT) has collapsed.
and metaplastic changes. Biliary epithelial dysplasia as well as in situ and invasive carcinoma may develop. Eventually, there is periductal or obliterative scar formation (Fig. 27-9). Peribiliary glands are often prominent, and when fibro-obliteration develops, their presence may indicate the site of a lost duct. Large areas of chronic inflammation and fibrosis may be present, particularly at the hilum, and they may simulate inflammatory myofibroblastic tumor (Fig. 27-10). There may be heavy infiltration of adjacent vascular structures (e.g., portal vein phlebitis). The combination of bile duct and vascular obstruction is probably responsible for the effacement of the lobar anatomy evident on gross examination, which manifests histologically as areas of parenchymal atrophy, extinction, fibrosis, and nodular regenerative hyperplasia.
Small Septal/Interlobular Bile Ducts
Figure 27-7. A septal bile duct is surrounded by an “onion skin”–like edematous concentric layer of fibrous stroma with admixed inflammatory cells.
Figure 27-8. Another example of “onion skin” periductal fibroinflammatory changes. 386
Needle biopsy samples may show changes secondary to cholangiodestruction and fibrosis of large ducts, direct involvement by the disease, or both. Direct involvement of small septal or interlobular bile ducts
Figure 27-10. Cellular fibrous stroma is permeated by lymphocytes and many plasma cells. Such areas may be extensive and may form well-defined masses. Inflammatory myofibroblastic (pseudo)tumor enters the differential diagnosis, particularly on biopsy specimens from such areas.
Primary Sclerosing Cholangitis inflammatory cell infiltrate and increased ductular profiles. Copperassociated protein may be demonstrated in periportal hepatocytes by orcein or Victoria blue stain (see Fig. 27-13B), sometimes in very small amount and focally. At later stages, biliary interface activity becomes more prominent, with florid ductular reaction and overt cholate stasis (Figs. 27-14 and 27-15).
27
Parenchymal Changes Cholate stasis consists of degenerative changes of hepatocytes at the limiting plate because of retention of bile salts. The changes include liver cell ballooning, Mallory hyaline formation, and more prominent accumulation of copper and copper-binding protein. With progression of the disease, portal-portal bridging fibrosis leads to cirrhotic transformation. Canalicular cholestasis is usually evident in end-stage livers. Its presence may indicate a dominant stricture, cholangiocarcinoma, or decompensation. Cholangiolar cholestasis may be seen in septic patients. Figure 27-11. An interlobular bile duct is directly involved by the inflammatory process. A bile duct of this size may be represented on a biopsy sample. The outline of the bile duct is irregular, and the epithelium is partly attenuated.
(Fig. 27-11) consists of cholangitis and/or pericholangitis, epithelial degenerative changes, attenuation and loss of bile duct epithelium, and periductal fibrosis (Fig. 27-12). “Onion skin” fibrosis may or may not be observed in fine needle biopsy specimens, because this change does not affect all ducts uniformly. Absence of “onion-skin” fibrosis in a fine needle biopsy specimen does not rule out PSC. On the other hand, it may be present in secondary sclerosing cholangitis (SSC) and should not be considered specific per se for a diagnosis of PSC. The late stage of the disease is characterized by fibrous scarring with disappearance of bile ducts, which are replaced by fibrous cords. Biliary remnants may be identified by immunohistochemistry for biliary cytokeratins (CK7, CK19, AE1/AE3).
Small Peripheral Portal Tracts Biopsy samples of peripheral liver often show changes secondary to injury of major bile ducts. Early indirect portal changes (Fig. 27-13) include mild portal fibrosis and edema, with a minimal mixed
Grading of Primary Sclerosing Cholangitis Four stages similar to those in primary biliary cirrhosis have been used to describe the evolution of PSC.29 At stage 1, changes are limited to portal tracts. At stage 2, there is involvement of the limiting plate with biliary interface activity. At stage 3, portal to portal fibrous linking occurs. At stage 4, there is cirrhosis.
Differential Diagnosis The diagnosis of PSC rests on close clinicopathologic correlation. The diagnostic criteria are similar in adults and children, but the differential diagnosis differs in these two age groups; the latter is discussed in Chapter 8. The differential diagnosis also depends on the stage of the disease. Subtle histologic changes suggestive of a cholangiopathy (see Fig. 27-13) may be seen at an early stage of the disease in liver biopsy specimens from patients with nonspecific abnormality of liver function tests or in patients suspected to be affected by other conditions. These changes are often dismissed as nonspecific, but they should raise the possibility of a cholangiopathy and warrant additional clinical investigations.
Primary Biliary Cirrhosis The pathologist may be asked to differentiate between PSC and primary biliary cirrhosis (PBC). On liver biopsy specimens, this distinction may be difficult and must rely on clinicopathologic correlation. PBC is more common in women and is associated with high levels of IgM and presence of antimitochondrial antibodies (AMAs), although cases of so-called “AMA-negative” PBC have been described. PBC is associated with autoimmune disorders such as sicca syndrome, thyroiditis, and arthritis. Cholangiography in PBC is often normal. Histologically, PBC is characterized by granulomatous cholangitis. The distinction between PBC and PSC is outlined in Table 26-4.
Autoimmune Hepatitis
Figure 27-12. With the increase of periductal fibrosis, the density of the peribiliary inflammation abates. Note the degenerative changes of the biliary epithelium.
The two conditions may overlap.30,31 Patients with an initial diagnosis of AIH may also show laboratory, cholangiographic, and/or histologic changes of a cholangiopathy.32,33 On the contrary, patients with an initial diagnosis of PSC may also fulfill criteria for AIH.18,34 One disease process may evolve into the other over time.35 The considerable zonal variation of the histologic changes in livers with PSC can be a source of confusion. In a patient with a clinical diagnosis of PSC, a biopsy sample from an area of parenchymal collapse 387
Practical Hepatic Pathology
A
B
C
D
Figure 27-13. Primary sclerosing cholangitis involving large hilar bile ducts. Liver biopsy samples of peripheral livers show indirect signs of the disease. (A) There is a slight ductular reaction with accompanying mild mixed inflammation. (B) Same portal tract as Figure 27-13A. Orcein stain shows focal dark-brown granules of copper-associated protein in periportal hepatocytes. (C) A small portal tract–like area shows a ductule and adjacent neutrophils. (D) Same case as Figure 27-13C. A different portal tract shows a more florid ductular reaction with an associated mild mixed inflammatory cell infiltrate.
Figure 27-14. Cholate stasis. Hepatocytes at the limiting plate show ballooning change and Mallory hyaline. There is ductular reaction in the adjacent stroma.
388
Figure 27-15. Cholate stasis: same field as in Figure 27-14. Orcein stain reveals abundant dark brown granules of copper-associated protein in hepatocytes at the limiting plate.
Primary Sclerosing Cholangitis or a patch of dense lymphoplasmacytic inflammation could raise the possibility of AIH. On the other hand, in a patient with clinically typical AIH, the presence of mild copper-associated protein deposition and ductular reaction could raise the possibility of a cholangiopathy. Once again, distinction relies on clinical, laboratory, serologic, and imaging findings. An autoimmune component is suggested by high titers of antinuclear and/or anti–smooth muscle antibodies, increased serum levels of immunoglobulin G (IgG), significantly elevated levels (3× normal) of AST and ALT, and, ultimately, clinical and laboratory response to immunosuppression. PSC, whether occurring by itself or in association with AIH, is diagnosed by significantly elevated (3× normal) biliary enzymes and cholangiographic findings. The overlap syndrome of PSC and AIH is discussed in Chapter 29.
IgG4-Related Sclerosing Cholangitis IgG4 is a subclass of IgG characterized by its low affinity for target antigen and inability to bind Clq. High serum IgG4 levels may be associated with atopic dermatitis, parasitic disease, and pemphigus.36 Patients with autoimmune or sclerosing pancreatitis have high IgG4 serum levels36 and many intrapancreatic and extrapancreatic IgG4-positive plasma cells by immunohistochemistry.37–41 The term IgG4-related systemic disease is now used to describe a syndrome characterized by increased serum IgG4 and multifocal IgG4positive sclerosing lymphoplasmacytic infiltrates responsive to steroid therapy.42,43 This disease typically involves the pancreas but can affect various other sites, including salivary glands, retroperitoneum, lymph nodes, kidneys, and the biliary tree.41,44 Involvement of the biliary tree (IgG4-related sclerosing cholangitis)44,45 manifests usually with obstructive jaundice and strictures of the intrapancreatic bile duct (51%) or the proximal extrahepatic/intrahepatic ducts (49%).42 Histologically, there is marked mural thickening of bile ducts by fibrosis and an associated dense lymphoplasmacytic infiltrate, with stenosis of the lumen. Obliterative phlebitis is characteristic. Immunohistochemistry shows many IgG4-positive plasma cells, even in peripheral portal tracts, which may be sampled by needle biopsy. Many eosinophils are present. The infiltrate involves peribiliary glands and nerves, but there is relative sparing of surface biliary epithelium. A review by Nakanuma and Zen provides a detailed description of IgG4 sclerosing cholangitis and the differential diagnosis with PSC.45 There is a tendency to develop inflammatory pseudotumor.45,46 IgG4-related sclerosing cholangitis responds to corticosteroids and recurs after withdrawal.
Hepatolithiasis and Recurrent Pyogenic Cholangitis These are typically diseases of the Far East but can be observed in Asian immigrants living in other countries. Hepatolithiasis is characterized by intrahepatic bilirubinate or cholesterol stone formation of uncertain cause. It can be complicated by superimposed bacterial infection and suppurative cholangitis. Recurrent pyogenic cholangitis is thought to be initiated by infestation with parasites such as Clonorchis sinensis, Opisthorchis viverrini, or Fasciola hepatica. Consequent cholangitis provokes biliary stone formation and superimposed bacterial infection with episodes of acute cholangitis.1 These two conditions overlap considerably and may show similarities to PSC. Of note, hepatolithiasis and suppurative cholangitis can be present in PSC.
Secondary Sclerosing Cholangitis PSC may be indistinguishable from secondary (acquired) sclerosing cholangitis (SSC) clinically, radiologically, and histologically. In adults, exclusion of secondary causes is requisite to establishing a diagnosis of
PSC; these include trauma, ischemia, surgery, chronic biliary infection in patients with primary or acquired immunodeficiency, rupture of hydatid cyst, irradiation, tumor, or portal vein pathology such as portal cavernoma with portal biliopathy.1 Of note, a previous history of biliary surgery or trauma does not rule out a preexistent clinically silent PSC. SSC is discussed further later in this chapter.
27
Other Chronic Liver Diseases Distortion of the biliary tree may occur in a range of acute and chronic liver diseases. A postmortem cholangiographic study of 154 livers of patients who did not have PSC showed that PSC-like cholangiographic changes were found frequently in cirrhosis, adult-type polycystic disease, submassive hepatic necrosis, metastatic carcinoma, and leukemia/ lymphoma infiltration.47
Dominant Stricture A minority of PSC patients (approximately 10% to 15%) develop a dominant stricture—a major obliteration at one point of the biliary tree with sudden worsening of jaundice. In these cases, the differential diagnosis is between an inflammatory stricture and cholangiocarcinoma. Tissue from dominant strictures may be obtained by fine needle biopsy or by bile duct brushing. The combination of biliary brushings and cancer antigen 19-9 may have diagnostic value.48 Special techniques may enhance the sensitivity of cytology for the diagnosis of cholangiocarcinoma.49
Genetics First-degree relatives of PSC patients have a 100-fold increased risk of developing the disease when compared with the general population.50 The inheritance pattern is complex, possibly because of the action of more than one gene.8 There is an association with HLA alleles,8,51–53 but other genes may be involved.11 In particular, the potential role of genes coding for hepatobiliary transporters is of interest. For example, patients with mutations of the ABCB4 gene encoding for the multidrug resistance P-glycoprotein 3 (MDR3) may develop cholangitis due to reduced formation of micelles and consequent detergent action of bile salts on biliary epithelium. The etiopathogenetic relationship of MDR3 mutations to PSC warrants further studies.54,55 An association between genetic variants of a natural killer cell receptor and its ligand and the risk of developing cholangiocarcinoma in PSC patients has been recently described.56,57
Treatment and Prognosis The clinical course is progressive with development of biliary cirrhosis. The median time from diagnosis to death or transplantation is reported to be 8 years.11 Disease progression occurs in the majority of patients who were asymptomatic at the time of diagnosis. Prognosis appears to be more favorable in patients with small duct disease.58–60 Prognostic models based on clinicopathologic parameters, including age, bilirubin level, histology, and presence of portal hypertension have been proposed.61–64 The severity of PSC does not correlate with the severity of the associated IBD, and treatment of one has little effect on the other.11 Complications include bacterial cholangitis, abscess formation, biliary duct stones, dominant stricture formation, and cholangiocarcinoma,65 as well as complications of IBD or other associated conditions. Ursodeoxycholic acid (UDCA) therapy can improve serum liver enzyme abnormalities, but the effect on symptoms, progression of fibrosis, and survival is controversial. Corticosteroids are of no use in patients with typical PSC but may be beneficial in patients who have an overlap syndrome with AIH. Dominant strictures are treated endoscopically.
389
Practical Hepatic Pathology The only potentially curative option is transplantation, but the disease is known to recur in the allograft. Cholangiocarcinoma can be discovered incidentally in a liver removed at transplantation, including in the gallbladder.27 The prevalence of cholangiocarcinoma in patients with PSC is between 7% and 13%.66 Patients with PSC at the cirrhotic stage are also at risk of developing hepatocellular carcinoma.67
Secondary (Acquired) Sclerosing Cholangitis SSC refers to cases of sclerosing cholangitis in which a possible etiologic factor can be recognized. A list of common causes is provided in Box 27-1. SSC has been shown to have poorer outcome than PSC.68 The biliary tree, unlike the liver, receives its blood supply entirely from the hepatic artery without a dual portal venous supply, making it susceptible to ischemia caused by hypotension or injury to the hepatic artery. In the liver allograft, ischemia is usually secondary to hepatic artery thrombosis or foamy cell arteriopathy as part of chronic rejection. The hepatic artery may appear patent radiologically.69 Superimposed bacterial or fungal infection with abscess formation may occur. Other causes of hepatic artery injury and SSC include ligation after abdominal trauma70 and intra-arterial infusion of floxuridine for the treatment of colorectal metastasis.71 A form of sclerosing cholangitis can occur in critically ill patients.72–74 Although severe trauma may have a direct effect, the pathogenesis is probably multifactorial, resulting from a combination of ischemia (e.g., arterial hypotension), superimposed infection by multiresistant bacteria,72 and bile cast formation. Infection of the biliary tree is the cause of SSC in patients with primary or secondary immunodeficiency. Ascending bacterial cholangitis, usually by gram-negative organisms, should be distinguished from the so-called “acquired immunodeficiency syndrome (AIDS) cholangiopathy.” The latter is seen in patients in advanced stages of AIDS, and its incidence is low where antiretroviral treatment is available.1 There may be intrahepatic or extrahepatic biliary involvement, gallbladder disease, and/or stenosis of the papilla of Vater. Histologic examination of the biliary tree may identify various organisms, sometimes in combination; the most frequent are cytomegalovirus and cryptosporidia (Cryptosporidium parvum), and occasionally microsporidia are found.75–77 C. parvum is considered to be the primary cause of AIDS cholangiopathy.78,79 Organisms are more easily seen in association with extrahepatic biliary tree epithelium, although cryptosporidia can be identified in interlobular bile ducts on liver biopsy. Cryptosporidium cholangiopathy has also been described in a renal transplant patient.80
Box 27-1. Secondary Causes of Sclerosing Cholangitis Ischemia Sclerosing cholangitis in critically ill patients (SC-CIP) Transarterial chemotherapy Arterial pathology in allograft Infection/infestation: primary/secondary immunodeficiency Cryptosporidium Cytomegalovirus Microsporidium Tumor Langerhans cell histiocytosis Systemic mastocytosis Other malignant tumors Other Mechanical obstruction by choledochal varices Trauma Radiation injury Hydatid (rupture, postinjection)
390
As many as 60% of children with primary immunodeficiency have sclerosing cholangitis.81 Children with primary immunodeficiency, in particular hyperIgM syndrome, develop cholangitis as well as acalculous cholecystitis,82 which is usually caused by cryptosporidium83 and sometimes by other microorganisms.84 This form of SSC may resolve after bone marrow transplantation85 but recurs after liver transplantation.86 Rupture of hydatid cysts, in particular after scolicidal injection, can result in a form of chemical SSC.87–89 In patients with portal vein obstruction, bypass venous collaterals (portal cavernoma) can compress the biliary tree,90,91 resulting in a form of SSC; intrahepatic lithiasis also occurs in this condition. SSC due to Langerhans cell histiocytosis has been observed in children92–94 and in adults.92,95 Patients with systemic mastocytosis have developed SSC.96,97 Radiation therapy for biliary or extrabiliary malignancy may result in biliary stricture formation.98–102 Suggested Readings Abdalian R, Heathcote EJ. Sclerosing cholangitis: a focus on secondary causes. Hepatology. 2006;44:1063–1074. Karlsen TH, Schrumpf E, Boberg KM. Genetic epidemiology of primary sclerosing cholangitis. World J Gastroenterol. 2007;13:5421–5431. LaRusso NF, Shneider BL, Black D, et al. Primary sclerosing cholangitis: summary of a workshop. Hepatology. 2006;44:746–764. Nakanuma Y, Zen Y. Pathology and immunopathology of immunoglobulin G4-related sclerosing cholangitis: the latest addition to the sclerosing cholangitis family. Hepatol Res. 2007;37(suppl 3):S478–S486. Portmann B, Nakanuma Y. Diseases of the bile ducts. In: MacSween RNM, Burt AD, Portmann B, et al, eds. MacSween’s Pathology of the Liver. 5th ed. London: Churchill Livingstone/Elsevier; 2007:973 x.
References 1. Abdalian R, Heathcote EJ. Sclerosing cholangitis: a focus on secondary causes. Hepatology. 2006;44:1063–1074. 2. Ludwig J. Small-duct primary sclerosing cholangitis. Semin Liver Dis. 1991;11:11–17. 3. Nikolaidis NL, Giouleme OI, Tziomalos KA, et al. Small-duct primary sclerosing cholangitis. A single-center seven-year experience. Dig Dis Sci. 2005;50:324–326. 4. Broome U, Bergquist A. Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer. Semin Liver Dis. 2006;26:31–41. 5. Takikawa H, Takamori Y, Tanaka A, et al. Analysis of 388 cases of primary sclerosing cholangitis in Japan: presence of a subgroup without pancreatic involvement in older patients. Hepatol Res. 2004;29:153–159. 6. Okazaki K. Is primary sclerosing cholangitis different from sclerosing cholangitis with autoimmune pancreatitis? J Gastroenterol. 2007;42:600–601. 7. Okazaki K, Uchida K, Matsushita M, et al. Autoimmune pancreatitis. Intern Med. 2005; 44:1215–1223. 8. Karlsen TH, Schrumpf E, Boberg KM. Genetic epidemiology of primary sclerosing cholangitis. World J Gastroenterol. 2007;13:5421–5431. 9. el Shabrawi M, Wilkinson ML, Portmann B, et al. Primary sclerosing cholangitis in childhood. Gastroenterology. 1987;92:1226–1235. 10. Feldstein AE, Perrault J, El Youssif M, et al. Primary sclerosing cholangitis in children: a long-term follow-up study. Hepatology. 2003;38:210–217. 11. LaRusso NF, Shneider BL, Black D, et al. Primary sclerosing cholangitis: summary of a workshop. Hepatology. 2006;44:746–764. 12. Lazaridis KN. Sclerosing cholangitis epidemiology and etiology. J Gastrointest Surg. 2008; 12:417–419. 13. Levy C, Lindor KD. Primary sclerosing cholangitis: Epidemiology, natural history, and prognosis. Semin Liver Dis. 2006;26:22–30. 14. Bjornsson E, Simren M, Olsson R, et al. Fatigue in patients with primary sclerosing cholangitis. Scand J Gastroenterol. 2004;39:961–968. 15. Steele IL, Levy C, Lindor KD. Primary sclerosing cholangitis—approach to diagnosis. Med Gen Med. 2007;9:20. 16. Bergquist A, Glaumann H, Lindberg B, et al. Primary sclerosing cholangitis can present with acute liver failure: report of two cases. J Hepatol. 2006;44:1005–1008. 17. Papatheodoridis GV, Hamilton M, Mistry PK, et al. Ulcerative colitis has an aggressive course after orthotopic liver transplantation for primary sclerosing cholangitis. Gut. 1998;43:639–644. 18. Mieli-Vergani G, Vergani D. Sclerosing cholangitis in the paediatric patient. Best Pract Res Clin Gastroenterol. 2001;15:681–690. 19. Kawaguchi K, Koike M, Tsuruta K, et al. Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas. Hum Pathol. 1991;22:387–395.
Primary Sclerosing Cholangitis 20. Angulo P, Peter JB, Gershwin ME, et al. Serum autoantibodies in patients with primary sclerosing cholangitis. J Hepatol. 2000;32:182–187. 21. Chapman R, Cullen S. Etiopathogenesis of primary sclerosing cholangitis. World J Gastroenterol. 2008;14:3350–3359. 22. Terjung B, Spengler U, Sauerbruch T, et al. “Atypical p-ANCA” in IBD and hepatobiliary disorders react with a 50-kilodalton nuclear envelope protein of neutrophils and myeloid cell lines. Gastroenterology. 2000;119:310–322. 23. Lindor KD. Characteristics of primary sclerosing cholangitis in the USA. Hepatol Res. 2007;37(suppl 3):S474–S477. 24. Tipnis NA, Werlin SL. The use of magnetic resonance cholangiopancreatography in children. Curr Gastroenterol Rep. 2007;9:225–229. 25. Kaw M, Silverman WB, Rabinovitz M, et al. Biliary tract calculi in primary sclerosing cholangitis. Am J Gastroenterol. 1995;90:72–75. 26. Toda K, Yasuda I, Nishigaki Y, et al. Inflammatory pseudotumor of the liver with primary sclerosing cholangitis. J Gastroenterol. 2000;35:304–309. 27. Lewis JT, Talwalkar JA, Rosen CB, et al. Prevalence and risk factors for gallbladder neoplasia in patients with primary sclerosing cholangitis: evidence for a metaplasia-dysplasia-carcinoma sequence. Am J Surg Pathol. 2007;31:907–913. 28. Ludwig J, Colina F, Poterucha JJ. Granulomas in primary sclerosing cholangitis. Liver. 1995;15:307–312. 29. Ludwig J, La Russo NF, Wiesner RH, et al. Primary sclerosing cholangitis. In: Peters R, Craig JR, eds. Liver Pathology: Contemporary Issues in Surgical Pathology. New York: Churchill Livingstone; 1986:193–213. 30. Gohlke F, Lohse AW, Dienes HP, et al. Evidence for an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis. J Hepatol. 1996;24:699–705. 31. McNair AN, Moloney M, Portmann BC, et al. Autoimmune hepatitis overlapping with primary sclerosing cholangitis in five cases. Am J Gastroenterol. 1998;93:777–784. 32. Gregorio GV, Portmann B, Karani J, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology. 2001;33:544–553. 33. Abdalian R, Dhar P, Jhaveri K, et al. Prevalence of sclerosing cholangitis in adults with autoimmune hepatitis: evaluating the role of routine magnetic resonance imaging. Hepatology. 2008;47:949–957. 34. Boberg KM, Fausa O, Haaland T, et al. Features of autoimmune hepatitis in primary sclerosing cholangitis: an evaluation of 114 primary sclerosing cholangitis patients according to a scoring system for the diagnosis of autoimmune hepatitis. Hepatology. 1996;23:1369–1376. 35. Abdo AA, Bain VG, Kichian K, et al. Evolution of autoimmune hepatitis to primary sclerosing cholangitis: a sequential syndrome. Hepatology. 2002;36:1393–1399. 36. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732–738. 37. Kamisawa T. IgG4-positive plasma cells specifically infiltrate various organs in autoimmune pancreatitis. Pancreas. 2004;29:167–168. 38. Kamisawa T, Egawa N, Nakajima H. Autoimmune pancreatitis is a systemic autoimmune disease. Am J Gastroenterol. 2003;98:2811–2812. 39. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38:982–984. 40. Kamisawa T, Funata N, Hayashi Y, et al. Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Gut. 2003;52:683–687. 41. Kamisawa T, Nakajima H, Egawa N, et al. IgG4-related sclerosing disease incorporating sclerosing pancreatitis, cholangitis, sialadenitis and retroperitoneal fibrosis with lymphadenopathy. Pancreatology. 2006;6:132–137. 42. Ghazale A, Chari ST, Zhang L, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology. 2008;134:706–715. 43. Masaki Y, Dong L, Kurose N, et al. Proposal for a new clinical entity, IgG4-positive multi-organ lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis. 2008; Epub. 44. Zen Y, Harada K, Sasaki M, et al. IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis? Am J Surg Pathol. 2004;28:1193–1203. 45. Nakanuma Y, Zen Y. Pathology and immunopathology of immunoglobulin G4-related sclerosing cholangitis: the latest addition to the sclerosing cholangitis family. Hepatol Res. 2007;37(suppl 3):S478–S486. 46. Toosi MN, Heathcote J. Pancreatic pseudotumor with sclerosing pancreato-cholangitis: is this a systemic disease? Am J Gastroenterol. 2004;99:377–382. 47. Terada T, Nakanuma Y. Intrahepatic cholangiographic appearance simulating primary sclerosing cholangitis in several hepatobiliary diseases: a postmortem cholangiographic and histopathological study in 154 livers at autopsy. Hepatology. 1995;22:75–81. 48. Furmanczyk PS, Grieco VS, Agoff SN. Biliary brush cytology and the detection of cholangiocarcinoma in primary sclerosing cholangitis: evaluation of specific cytomorphologic features and CA19-9 levels. Am J Clin Pathol. 2005;124:355–360. 49. Moreno Luna LE, Kipp B, Halling KC, et al. Advanced cytologic techniques for the detection of malignant pancreatobiliary strictures. Gastroenterology. 2006;131:1064–1072. 50. Bergquist A, Lindberg G, Saarinen S, et al. Increased prevalence of primary sclerosing cholangitis among first-degree relatives. J Hepatol. 2005;42:252–256. 51. Donaldson PT, Farrant JM, Wilkinson ML, et al. Dual association of HLA DR2 and DR3 with primary sclerosing cholangitis. Hepatology. 1991;13:129–133.
52. Donaldson PT, Norris S. Evaluation of the role of MHC class II alleles, haplotypes and selected amino acid sequences in primary sclerosing cholangitis. Autoimmunity. 2002;35:555–564. 53. Neri TM, Cavestro GM, Seghini P, et al. Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population. Dig Liver Dis. 2003;35:571–576. 54. Trauner M, Fickert P, Wagner M. MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. Semin Liver Dis. 2007;27:77–98. 55. Pauli-Magnus C, Kerb R, Fattinger K, et al. BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology. 2004; 39:779–791. 56. Melum E, Karlsen TH, Schrumpf E, et al. Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms. Hepatology. 2008;47:90–96. 57. Lazaridis KN. Dissecting the genetic susceptibility for cholangiocarcinoma in primary sclerosing cholangitis. Hepatology. 2008;47:8–10. 58. Bjornsson E, Boberg KM, Cullen S, et al. Patients with small duct primary sclerosing cholangitis have a favorable long term prognosis. Gut. 2002;51:731–735. 59. Angulo P, Maor-Kendler Y, Lindor KD. Small-duct primary sclerosing cholangitis: a long-term follow-up study. Hepatology. 2002;35:1494–1500. 60. Broome U, Glaumann H, Lindstom E, et al. Natural history and outcome in 32 Swedish patients with small duct primary sclerosing cholangitis (PSC). J Hepatol. 2002;36:586–589. 61. Broome U, Olsson R, Loof L, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut. 1996;38:610–615. 62. Farrant JM, Hayllar KM, Wilkinson ML, et al. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology. 1991;100:1710–1717. 63. Kim WR, Therneau TM, Wiesner RH, et al. A revised natural history model for primary sclerosing cholangitis. Mayo Clin Proc. 2000;75:688–694. 64. Neuberger J, Gunson B, Komolmit P, et al. Pretransplant prediction of prognosis after liver transplantation in primary sclerosing cholangitis using a Cox regression model. Hepatology. 1999;29:1375–1379. 65. Burak K, Angulo P, Pasha TM, et al. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2004;99:523–526. 66. Lazaridis KN, Gores GJ. Primary sclerosing cholangitis and cholangiocarcinoma. Semin Liver Dis. 2006;26:42–51. 67. Harnois DM, Gores GJ, Ludwig J, et al. Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer? J Hepatol. 1997;27:512–516. 68. Gossard AA, Angulo P, Lindor KD. Secondary sclerosing cholangitis: a comparison to primary sclerosing cholangitis. Am J Gastroenterol. 2005;100:1330–1333. 69. Buis CI, Hoekstra H, Verdonk RC, et al. Causes and consequences of ischemic-type biliary lesions after liver transplantation. J Hepatobiliary Pancreat Surg. 2006;13:517–524. 70. Martin de Carpi M, Tarrado X, Varea V. Sclerosing cholangitis secondary to hepatic artery ligation after abdominal trauma. Eur J Gastroenterol Hepatol. 2005;17:987–990. 71. Barnett KT, Malafa MP. Complications of hepatic artery infusion: a review of 4580 reported cases. Int J Gastrointest Cancer. 2001;30:147–160. 72. Gelbmann CM, Rummele P, Wimmer M, et al. Ischemic-like cholangiopathy with secondary sclerosing cholangitis in critically ill patients. Am J Gastroenterol. 2007;102:1221–1229. 73. Jaeger C, Mayer G, Henrich R, et al. Secondary sclerosing cholangitis after long-term treatment in an intensive care unit: clinical presentation, endoscopic findings, treatment, and follow-up. Endoscopy. 2006;38:730–734. 74. Benninger J, Grobholz R, Oeztuerk Y, et al. Sclerosing cholangitis following severe trauma: description of a remarkable disease entity with emphasis on possible pathophysiologic mechanisms. World J Gastroenterol. 2005;11:4199–4205. 75. Sheikh RA, Prindiville TP, Yenamandra S, et al. Microsporidial AIDS cholangiopathy due to Encephalitozoon intestinalis: case report and review. Am J Gastroenterol. 2000; 95:2364–2371. 76. Liberman E, Yen TS. Foamy macrophages in acquired immunodeficiency syndrome cholangiopathy with 'PEGRJCNKVQ\QQPKPVGUVKPCNKU. Arch Pathol Lab Med. 1997;121:985–988. 77. Willson R, Harrington R, Stewart B, et al. Human immunodeficiency virus 1-associated necrotizing cholangitis caused by infection with 5GRVCVC KPVGUVKPCNKU. Gastroenterology. 1995;108:247–251. 78. Chen XM, LaRusso NF. Cryptosporidiosis and the pathogenesis of AIDS-cholangiopathy. Semin Liver Dis. 2002;22:277–289. 79. Alpini G, McGill JM, LaRusso NF. The pathobiology of biliary epithelia. Hepatology. 2002;35:1256–1268. 80. Abdo A, Klassen J, Urbanski S, et al. Reversible sclerosing cholangitis secondary to cryptosporidiosis in a renal transplant patient. J Hepatol. 2003;38:688–691. 81. Rodrigues F, Davies EG, Harrison P, et al. Liver disease in children with primary immunodeficiencies. J Pediatr. 2004;145:333–339. 82. Lin SC, Shyur SD, Ma YC, et al. Recurrent acalculous cholecystitis and sclerosing cholangitis in a patient with X-linked hyper-immunoglobulin M syndrome. J Formos Med Assoc. 2005;104:421–426. 83. Winkelstein JA, Marino MC, Ochs H, et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore). 2003;82:373–384. 84. Bhatia V, Garg PK, Agarwal V, et al. Inflammatory papillary stenosis due to )KCTFKCNCODNKC in a patient with hyper-immunoglobulin M immunodeficiency syndrome. Gastrointest Endosc. 2007;66:181–182.
27
391
Practical Hepatic Pathology 85. Dimicoli S, Bensoussan D, Latger-Cannard V, et al. Complete recovery from %T[RVQURQTKFKWO RCTXWO infection with gastroenteritis and sclerosing cholangitis after successful bone marrow transplantation in two brothers with X-linked hyper-IgM syndrome. Bone Marrow Transplant. 2003;32:733–737. 86. Levy J, Espanol-Boren T, Thomas C, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr. 1997;131:47–54. 87. Tsimoyiannis EC, Grantzis E, Moutesidou K, et al. Secondary sclerosing cholangitis: after injection of formaldehyde into hydatid cysts in the liver. Eur J Surg. 1995;161:299–300. 88. Taranto D, Beneduce F, Vitale LM, et al. Chemical sclerosing cholangitis after injection of scolicidal solution. Ital J Gastroenterol. 1995;27:78–79. 89. Castellano G, Moreno-Sanchez D, Gutierrez J, et al. Caustic sclerosing cholangitis. Report of four cases and a cumulative review of the literature. Hepatogastroenterology. 1994;41:458–470. 90. Khuroo MS, Yattoo GN, Zargar SA, et al. Biliary abnormalities associated with extrahepatic portal venous obstruction. Hepatology. 1993;17:807–813. 91. Dilawari JB, Chawla YK. Pseudosclerosing cholangitis in extrahepatic portal venous obstruction. Gut. 1992;33:272–276. 92. Jaffe R. Liver involvement in the histiocytic disorders of childhood. Pediatr Dev Pathol. 2004;7:214–225. 93. Braier J, Ciocca M, Latella A, et al. Cholestasis, sclerosing cholangitis, and liver transplantation in Langerhans cell histiocytosis. Med Pediatr Oncol. 2002;38:178–182.
392
94. Zandi P, Panis Y, Debray D, et al. Pediatric liver transplantation for Langerhans’ cell histiocytosis. Hepatology. 1995;21:129–133. 95. Griffiths W, Davies S, Gibbs P, et al. Liver transplantation in an adult with sclerosing cholangitis due to Langerhans cell histiocytosis. J Hepatol. 2006;44:829–831. 96. Baron TH, Koehler RE, Rodgers WH, et al. Mast cell cholangiopathy: another cause of sclerosing cholangitis. Gastroenterology. 1995;109:1677–1681. 97. Marbello L, Anghilieri M, Nosari A, et al. Aggressive systemic mastocytosis mimicking sclerosing cholangitis. Haematologica. 2004;89:ECR35. 98. Di Fiore F, Savoye-Collet C, Savoye G, et al. Magnetic resonance cholangiographic assessment of a delayed radiation-induced bile duct stricture. Dig Liver Dis. 2001;33:584–586. 99. Nakakubo Y, Kondo S, Katoh H, et al. Biliary stricture as a possible late complication of radiation therapy. Hepatogastroenterology. 2000;47:1531–1532. 100. Cherqui D, Palazzo L, Piedbois P, et al. Common bile duct stricture as a late complication of upper abdominal radiotherapy. J Hepatol. 1994;20:693–697. 101. Halevy A, Adam A, Stamp G, et al. Radiation stricture of the biliary ducts: an emerging new entity? HPB Surg. 1992;5:267–270. 102. Martenson Jr JA, Gunderson LL, Buskirk SJ, et al. Hepatic duct stricture after radical radiation therapy for biliary cancer: recurrence or fibrosis? Mayo Clin Proc. 1986;61:530–536.