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

Primary Sclerosing Cholangitis - Diseases of the Liver

PSC is a chronic liver disease that is char-acterized by chronic inflammation and obliterative fibrosis of the intra- and extra-hepatic bile ducts.

Primary Sclerosing Cholangitis


PSC is a chronic liver disease that is char-acterized by chronic inflammation and obliterative fibrosis of the intra- and extra-hepatic bile ducts. Similar to PBC, the bile ducts are the initial target of injury with subsequent hepatic injury and progres-sion to liver failure. Unlike PBC, there is a great deal more uncertainty as to the opti-mal means of diagnosis, monitoring, and therapy. Although the exact cause of PSC is unknown, it is considered autoimmune due to the presence of autoantibodies. However, therapy is limited because PSC does not respond as well to conventional immunosuppressive therapies as do other autoimmune diseases.


PSC typically presents in the fourth to fifth decades of life. Men are affected more often than women, which is in contrast to PBC. Patients often present with pruritis and fatigue. Essentially, the clinical course represents a progressive worsening of symptoms associated with bile stasis and eventual development of jaundice and end-stage liver disease. About a third of patients have bacterial cholangitis, especially fol-lowing biliary intervention, during which time the disease can progress. In addition, PSC is closely related to IBD (typically UC) and 10 percent of patients develop cholan-giocarcinoma, which can occur relatively early, before the onset of cirrhosis.


Similar to PBC, patients exhibit abnor-malities in liver enzymes, characteristic histologic findings, and serum autoanti-bodies. However, the diagnosis of PSC requires demonstration of a “beaded” pattern by endoscopic retrograde cholan-giopancreatography (ERCP) or magnetic resonance cholangiopancreatography, which represents alternating areas of stric-ture and dilatation of the bile ducts.


The primary injury is against medium-and large-sized bile ducts. The smaller ducts gradually disappear as a result of obstruction. The classic, nearly pathogno-monic, lesion of PSC is concentric periduc-tal fibrosis (onion-skinning) that causes narrowing and obliteration of the small bile ducts, ultimately leaving a scar. Other nonspecific changes commonly seen in chronic cholestasis include pseudoxantho-matous changes, Mallory bodies, and peri-portal copper accumulation. The staging and grading of PSC has not been tested for reliability. But similar to PBC, four stages have been described.


The autoimmune nature of PSC is sup-ported by the presence of hypergamma-globulinemia, multiple autoantibodies, and specific MHC haplotypes commonly associated with autoimmune diseases. As mentioned earlier, it is also associated with other immune-mediated inflammatory dis-orders such as IBD. While many autoanti-bodies may be present in PSC, it is most closely linked to perinuclear antineutro-phil cytoplasmic antibody (pANCA). Stud-ies suggest that the antigen targeted by pANCA is either a nuclear envelope pro-tein, myeloid-specific tubulin-beta isotype 5, or histone H1. These antibodies do not appear to be directly cytotoxic.


A recent study has suggested that the association between IBD and PSC is the result of inappropriate recruitment of mucosal lymphocytes to extraintesti-nal tissue. In PSC, the mucosal addressin, MAdCAM-1 and the gut-specific chemo-kine, CCL25, which are normally present in the intestine, are aberrantly expressed in the liver where they recruit mucosal lym-phocytes. As a result, in PSC, the liver is infiltrated by activated mucosal T cells that secrete pro-inflammatory cytokines. The activated T cells bind to biliary epithelial cells. Whether this process represents a pri-mary or a secondary change is not clear. In other studies, it has been suggested that toll-like receptors (TLRs), involved in the trig-gering of innate immune responses in IBD, may also play a role in the pathogenesis of PSC. TLRs are expressed in both gastroin-testinal epithelial cells and cholangiocytes. It is possible that activation of TLRs can manipulate transepithelial resistance and decrease epithelial barrier function.


Unfortunately, no animal models are able to fully demonstrate the spectrum of clinical and pathological features of PSC. Although various toxins can induce chol-angiocyte injury in rodents, the end result does not adequately mimic human dis-ease. One model that shows promise is that of the Mdr2 knockout mouse. Normal bile secretion depends on the presence of bile acid and lipid transporters. In humans, MDR3/ABCB4 (the murine analog is Mdr2) encodes a canalicular flipase that is respon-sible for transporting phospholipids into bile. Humans with MDR3 mutations have been found to develop progressive famil-ial intrahepatic cholestasis. Mice that have Mdr2 knocked out have spontaneous scle-rosing cholangitis with serum as well as histologic features resembling human PSC. These mice also develop autoantibodies to pANCA. These mice have been utilized as models for therapy in PSC. In this model, nor-ursodeoxycholic acid improved histo-logic findings and liver enzymes.


The improvement in PSC using ursode-oxycholic acid is controversial. While there may be an improvement in liver enzymes, there is no actual improvement in liver histology or liver transplant-free survival. Between 10 and 15 percent of patients with PSC will experience high-grade obstruc-tion from a discrete area of narrowing within the extrahepatic tree. In the past, these were managed surgically. Since then, improvements in endoscopic techniques have allowed for management by ERCP with balloon or coaxial dilatation or stent-ing. Clinical response can be achieved in 80 percent of patients without cirrhosis. Liver transplant survival is excellent with 90 per-cent at one year and 84 percent at two years. Retransplantation rates are higher for PSC patients than those with other diagnoses (9.6 percent versus 4.6 percent within two years) potentially due to the persistence of underlying immunologic defects.


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