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Chapter: Essential Clinical Immunology: Immunological Aspects of Gastrointestinal and Liver Disease

Primary Biliary Cirrhosis - Diseases of the Liver

Primary biliary cirrhosis (PBC) is an auto-immune disease of the liver that results in chronic injury to the intrahepatic bile duct epithelium.

Primary Biliary Cirrhosis


Primary biliary cirrhosis (PBC) is an auto-immune disease of the liver that results in chronic injury to the intrahepatic bile duct epithelium. The gradual destruction of the bile ducts causes cholestasis with the sub-sequent retention of toxins, inciting further hepatic injury and resulting in fibrosis, cirrhosis, and eventual liver failure. Early detection is optimal, before significant liver injury has occurred.


PBC primarily affects middle-aged women. The ratio of affected women to men has been reported to be as high as 9:1.

The most common presenting symptoms include pruritis and fatigue. While pruritis can be severe, there is marked improve-ment by medications such as ursodiol. Fatigue on the other hand causes signifi-cant disability, as there are no medications that can provide relief. Other findings may include hyperlipidemia and osteo-porosis. In addition, patients may have concurrent autoimmune diseases, which include but are not limited to Sjögren’s syndrome and scleroderma. Patients with more advanced disease may present with symptoms commonly seen with other chronic liver diseases such as ascites, por-tal hypertension, and esophageal varices. An increased incidence of HCC in patients with longstanding advanced disease has been described.


The diagnostic criteria for PBC include an elevation in liver enzymes (most nota-bly alkaline phosphatase) for a duration of six or more months, histologic findings, and the presence of antimitochondrial antibodies in the serum. The presence of two criteria is highly suggestive of the disease while a definite diagnosis requires all three.


Involvement of the liver is heteroge-neous, so a biopsy may demonstrate dif-ferent stages of disease. In such instances, the disease is assigned the most advanced stage. Stage I is characterized by portal inflammation comprised of predomi-nantly lymphoplasmacytic infiltrates. The pathognomonic lesion of PBC, the florid duct lesion, represents focal duct oblitera-tion by granuloma formation. In stage II there is extension of inflammation to the periportal areas. There is formation of fibrous septa that link adjacent portal tri-ads and bile duct loss (ductopenia) in stage III. Finally, stage IV is defined by frank cirrhosis.

The targets of the antimitochondrial antibodies belong to the family of 2-oxo-acid dehydrogenase enzyme complexes located in the inner mitochondrial mem-brane. The major autoantigen is the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). Given that 90 to 95 percent of patients with PBC have anti-mitochondrial antibodies, some of which are asymptomatic, serologic detection has allowed for earlier diagnosis of disease and improvement in prognosis.


Molecular mimicry is the most widely proposed explanation as to the induction of autoimmunity in PBC. Briefly, a host is infected with a microorganism that con-tains antigens similar to antigens present in the host. These microbial antigens induce an immunologic response when presented to the immune system of the host. As a result, what began as a pathogen-specific response then cross-reacts with the host antigens and results in tissue injury and disease. This mechanism has also been associated with other autoimmune dis-eases of the liver such as primary scleros-ing cholangitis (PSC) and autoimmune hepatitis (AIH).


Bacteria such as Escherichia coli have been implicated due to the reported high incidence of urinary tract infec-tions in patients with PBC. Antibodies against human pyruvate dehydrogenase in PBC patients react well against the E. coli pyruvate dehydrogenase complex. More recently, a Gram-negative aerobe,


Novosphingobium aromaticivorans has been demonstrated to have an even higher degree of homology with the immunodominant epitope on human PDC-E2 than E. coli. The titers of antibodies in PBC patients against pyruvate dehydrogenase in N. aromaticiv-orans are as much as 1,000 times higher than the titers of antibody against E. coli.

Other potential infectious triggers include


Chlamydia pneumoniae and lactobacilli.


The exact mechanism of biliary destruc-tion is not entirely clear, as it appears that the autoantibodies do not have a direct cytotoxic effect. This is supported by a lack of correlation between antibody titer and extent of hepatic involvement, the lack of immediate recurrence despite the persis-tence of antibodies status post-liver trans-plantation, and the absence of antibodies in about 5–10 percent of patients with histo-logically confirmed PBC.


The involvement of inflammatory cells in the pathogenesis of PBC is supported by several findings. The epitopes recognized by portal CD4+ helper and CD8+ cyto-toxic T cells overlap on the lipoyl domain of PDC-E2. In patients with PBC, studies have demonstrated that the frequency of autoreactive CD4+ T cells is higher in the hepatic lymph nodes than in the circula-tion. In addition, CD8+ T cells and B cells that are reactive with PDC-E2 are higher in the liver than in the circulation. A decrease in CD4+ CD25-high regulatory (Treg) cells may also contribute to an acceleration of autoimmunity in PBC. Bile duct destruc-tion secondary to the accumulation of bile acids is thought to play a role in dis-ease progression. Cholestasis increases the expression of HLA class I antigens in hepa-tocytes in PBC. The implication here is that there is increased presentation of antigens to cytotoxic cells.


Some puzzling observations are that the autoantibodies are specifically directed against the mitochondria in bile duct epi-thelial cells despite the fact that nucle-ated cells are ubiquitous in the body. One proposed theory is that the altered state of apoptotic biliary epithelial cells predis-poses them to having antibodies devel-oped against them. It is thought that the  blockage of glutathione attachment to the lysine-lipoyl moiety of the E2 protein during biliary epithelial cell apoptosis ren-ders the PDC-E2 susceptible to recognition by autoantibodies. When compared with PSC, the injury is limited to the intrahepatic ducts in PBC. The extrahepatic ducts often remain intact even at the cirrhotic stage. This selectivity for cholangiocytes may be attributed to inherent genetic differences (observed in mice) present in intra- and extrahepatic cholangiocytes.


Recently, studies have identified three murine models that spontaneously develop PBC. These models include the NOD.c3c4 mouse, a mouse with the domi-nant negative form of tTGF-β receptor II (dnTGFβ RII), and the IL-2Rα knockout mouse. In all three models, the target of the antimitochondrial antibodies is PDC-E2 and the immunodominant epitope is the lipoyl domain. In addition, they all dem-onstrate lymphocyte infiltration around the portal tracts accompanied by chol-angiocyte injury. These animal models could help elucidate many unanswered questions.


Medical therapy is geared toward both symptomatic improvement and treatment of underlying disease. Cholestyramine and rifampin are common agents used to treat the pruritis. Ursodiol (ursodeoxycho-lic acid) is the only medical treatment for PBC that has received approval by the U.S. Food and Drug Administration. Ursodiol has been found to cause a normalization of enzymes and improve histologic find-ings in approximately 25 to 30 percent of patients with PBC. In addition, at least 20 percent of patients treated with ursodiol have no histologic progression over four years. Its effects are thought to be mul-tifactorial. It promotes both endogenous bile acid secretion and membrane stabilization. This compound is also associated with reduced aberrant HLA type 1 expres-sion on hepatocytes and a fall in cytokine production. Colchicine and methotrexate are also commonly utilized if there is inad-equate response to ursodeoxycholic acid. PBC still remains one of the top five indica-tions for liver transplantation. The survival rates are 92 percent and 85 percent at one and five years, respectively. PBC recurs in 15 percent of patients at three years and 30 percent at ten years.


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