Section 1 -

Update on Primary Biliary Cirrhosis & Primary Sclerosing Cholangitis Swan N. Thung Professor of Pathology, and Gene & Cell Medicine Mount Sinai School of Medicine New York, NY

Primary biliary cirrhosis (PBC) [1, 2, 3] and primary sclerosing cholangitis (PSC) [4, 5] are chronic biliary duct diseases, which progress eventually to biliary cirrhosis. Their etiology is unknown, but both are probably immune–mediated disorders. Patients with PBC or PSC often present with elevated canalicular enzyme (alkaline phosphatase and gamma-glutamyl transferase) activities with or without pruritus. The rest of the clinical picture and laboratory test results of patients with PBC or PSC are characteristic, and the differentiation between the two is often not difficult. In some patients, however, they are less typical and liver biopsy is needed. The clinical and pathologic differential diagnoses are described. Etiology Evidence suggests the role of genetic, immunologic, and infective factors in the development of both diseases. PBC is associated with autoimmune conditions such as thyroid disease, sicca complex, rheumatoid arthritis, dermatomyositis, systemic lupus erythematosus, CREST syndrome, and autoimmune hemolytic anemia; and with the presence of anti-mitochondrial antibodies (AMA), which are directed at the E2 component of pyruvate dehydrogenase (PDC-E2), located on the inner mitochondrial membrane. The relationship of mitochondrial antigens and antibodies to the pathogenesis of PBC has always been speculative. PDC-E2 complex has been expressed on the bile duct epithelium of patients with early PBC [6]. Injection of AMA M2 autoantigen into a mouse model produced AMA M2 autoantibodies and bile duct degeneration in these mice [7]. Furthermore, spontaneous autoimmune biliary disease, which serologically and pathogenetically mimicked PBC was recently described in NOD.c3c4 congenic mice [8]. The latter mouse model in addition to the deficient CD4+CD25+ regulatory T cells (Tregs) in patients with PBC as well as in their daughters and sisters, support a genetic factor in the pathogenesis of PBC [9]. PBC has been reported in sisters, twins, mothers and daughters. In addition, there is increased prevalence of HLA-DRw8 and C4A-QO in patients with PBC in the US. The prevalence of circulating AMA is increased in relatives of patients. The AMA in patients with PBC cross-reacts with subcellular constituents of Gram-negative and positive organisms, and the etiological role of enterobacterial antigens in intestinal infection and Gram negative urinary infections have been suggested [10]. PSC is associated with ulcerative colitis (UC) in 70% of patients. Rarely, it is associated with regional ileitis. The manifestation of PSC may precede that of ulcerative colitis. The prevalence of PSC among patients with UC is about 5%. An increased prevalence of certain HLA haplotypes (A1, B8, DR3, DR4, and DRW52A) is seen [11]. Perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are found in majority of patients. Increased intercellular adhesion molecule-1 concentration in the serum also suggests activation of patients' immune system [12]. Increases in serum levels of circulating immune complexes and in complement metabolism, in addition to their association with other autoimmune diseases, such as thyroiditis and type1diabetes, further support the role of immunologic factors in PSC. It is, however, unclear whether these immunologic changes actually cause PSC or are simply epiphenomena. Infection of the biliary tree by microsporidium or Cryptosporidium results in cholangiographic and histologic changes of PSC. This suggests that UC, which may cause leakage of bacteria or bacterial products through damaged intestinal epithelium to the portal vein, may have the same effect. Clinical Features Ninety percent of patients with PBC are women, usually 40-60 years of age. Patients may be asymptomatic or may complain of pruritus, fatigue, or right upper quadrant pain. Hepatomegaly, skin xanthomas, scratching marks on the skin, complains of backache and pain over the ribs from bone changes associated with chronic cholestasis, and bleeding duodenal varices may be observed. Immune mediated diseases as mentioned earlier are frequently associated with PBC [13, 14]. PSC affects predominantly men between 25-45 years, but can also occur in children as young as 2 years [4, 15, 16]. It is no longer accurate to regard PSC as rare in children. Childhood PSC usually presents in mid-childhood to early adolescence [17]. Patients may be asymptomatic or experiencing fatigue, right upper quadrant pain, pruritus and intermittent jaundice. Symptoms indicate advanced disease. Most children present with nonspecific symptoms and in approximately 80% do not present with jaundice. Serum alkaline phosphatase activity is persistently elevated, even in asymptomatic patients. Fever with or without jaundice accompanies ascending cholangitis, which complicates biliary surgery, endoscopy or occurs spontaneously. The ductal disease progresses eventually to biliary cirrhosis with its complications, i.e. portal hypertension and/or hepatocellular failure [2]. In the overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis, the aminotransferase activities are higher, and the autoimmune hepatitis component usually responds to immunosuppressive treatment [10]. Autoimmune hepatitis is an important "atypical" clinical picture of childhood PSC, frequently with elevated IgG, and positive anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA), in addition to features of cholestasis and bile duct disease. Clinical response to corticosteroids in childhood PSC may be equivocal or incomplete [18]. Laboratory Findings Bile canalicular enzymes, e.g. alkaline phosphatase and gamma-glutamyl transferase are elevated in the serum in both conditions. Serum copper, ceruloplasmin and liver copper content are also increased owing to chronic cholestasis. Serum IgM is almost always elevated in PBC and in 50% of patients with PSC. Bilirubin values are normal in the beginning and will rise at later stages of the disease. Low titers of ANA and ASMA are present in both diseases. AMA with titers above 1:40 is characteristic for PBC, while pANCA is found in at least two-thirds of patients with PSC [19]. Cholangiography PSC is readily diagnosed by the appearance on endoscopic retrograde cholangiopancreatography (ERCP) as areas of irregular stricture formation and dilatation (beading) involving the intrahepatic and/or extrahepatic bile ducts [20]. If the disease involves only the small bile ducts (small duct PSC), the ERCP appearance is similar to that of PBC, which is normal. Magnetic resonance (MR) cholangiopancreatography is also considered diagnostic technique for this disease [21], but its interpretation may be difficult in smaller children. Liver Pathology The histological appearances of PBC have been divided into 4 stages: stage 1 florid duct lesion; stage 2 ductular reactions; stage 3 scarring (septal fibrosis and bridging); stage 4 cirrhosis [22]. Staging of PBC, however, has its shortcomings, because the changes in the liver are focal, the different stages may overlap, and there is no good correlation between the clinical picture and the stage. The only diagnostic histological finding is the florid duct lesion (stage 1), in which the bile duct epithelial cells are swollen or exhibit eosinophilic degeneration, irregular and the underlying basement membrane is disrupted [23]. This damaged bile duct is surrounded by a cellular reaction, which includes lymphocytes, plasma cells, histiocytes and some eosinophils. Granulomas may be observed around the ruptured bile ducts and in the lobules. Following the destruction, the bile ducts disappeared and the bile ductules begin to proliferate (stage 2). Hepatic arterial branches can be identified without the accompanying bile ducts. Loss of bile ducts results in changes of prolonged cholestasis e.g. increased copper and copper-binding protein, cholate-stasis (ballooning), and Mallory hyalin in periportal hepatocytes. Fibrosis extends from and connects adjacent portal tracts (stage 3). With increased fibrosis, the inflammatory cells will decrease. Eventually, fibrous septa surround regenerative nodules (stage 4). There may be variable degree of interface hepatitis and lobular inflammation. When they are significant, an overlap of PBC and autoimmune hepatitis has to be considered. Nodular regenerative hyperplasia has been described even in early stages of PBC. Liver changes, especially in the earlier stages of PSC are non-specific and may be difficult to differentiate from chronic hepatitis. Biopsy specimens show fibrosis and lymphocytic infiltration of portal tracts with atrophy of bile ducts. The portal inflammation is always less than what is seen in PBC. PSC is a fibro-inflammatory disease of bile ducts, resulting in periductal "onion-skin" fibrosis, bile duct scars, and cholangiectases [24]. Other changes secondary to the chronic bile duct disease and cholestasis are similar to those seen in PBC, i.e. cholestasis, cholate-stasis, increased levels of copper and copper-binding protein in periportal and periseptal hepatocytes, ductular reaction and eventually biliary cirrhosis. Acute cholangitis may complicate PSC. Secondary sclerosing cholangitis presents with the same histopathologic changes as PSC. Secondary causes, including postoperative biliary stricture, ischemic cholangitis due to intrahepatic chemoembolization, hepatic arterial thrombosis following liver transplantation, AIDS-related cholangiopathy, bile duct neoplasm, Langerhans cell histiocytosis, and cystic fibrosis can usually be excluded by the patient's history, physical examination, and laboratory tests. Prognosis The course is variable and unpredictable in both diseases, particularly among the asymptomatic patients. Prognostic models in PBC are based on Cox's regression analysis, which depends on age, serum albumin and bilirubin levels, prothrombin time, and the presence or absence of edema [25]. Hepatocellular carcinoma, lymphoma and breast carcinoma are malignancies sometimes associated with PBC [26, 27]. PSC with involvement of extra-hepatic ducts has a worse prognosis than intra-hepatic alone. PSC with normal cholangiography (=small duct PSC) gives better overall transplantation-free survival than large duct PSC. The level of serum bilirubin, histological stage of the fibrosis, age, sex (women have poorer prognosis than men) and the presence of splenomegaly (portal hypertension) are factors that influence survival. Sclerosing cholangitis, in addition, is a risk factor for cholangiocarcinoma. A small group of patients may do well, but the majority of patients suffer from cholestatic jaundice, portal hypertension with variceal bleeding, liver failure and cholangiocarcinoma. Cholangiocarcinoma may develop in approximately 10% of patients with PSC. Treatment There is no specific treatment for PBC or PSC. Control of itching and replacement of fat-soluble vitamins is important in jaundiced patients. Ursodeoxycholic acid (UDCA) has been shown to improve the biochemical expression of liver damage in patients with cholestatic liver diseases [28, 29]. In some studies, histology was shown to improve, and treatment for at least 2 years, prolonged survival in one study [30]. Other treatments using methotrexate, immunosuppressive drugs, colchicine, etc, have been tried in PBC with little or no benefits [31, 32]. Bacterial cholangitis in PSC is treated with broad-spectrum antibiotics. Local strictures in major bile ducts may be relieved by introduction of stents, using balloon dilation via transhepatic or endoscopic routes [33]. Liver transplantation should be considered for patients with uncontrollable itching, ascites, hepatic encephalopathy, and bleeding esophageal varices. Timing of liver transplantation is important Results are excellent in PBC with 1 year survival about 85-90% and a 5 year survival of 60-70%. Recurrence of PBC in the allografts ranges between 5-35% [34, 35, 36, 37]. Recurrence of PSC in the allograft has been reported [38, 39]. 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