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Current Concepts in Primary Sclerosing Cholangitis

  • RUSSELL H. WIESNER
    Correspondence
    Address reprint requests to Dr. R. H. Wiesner, Division of Gastroenterology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905
    Affiliations
    Division of Gastroenterology and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota
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      Objective

      To describe primary sclerosing cholangitis (PSC) and its associated complications, as well as medical and surgical treatment.

      Design

      A review of PSC and its associated etiopathologic factors is presented; numerous studies of agents that are used to treat patients with PSC are discussed.

      Results

      PSC, a slowly progressive disease that often involves autoimmune damage to the biliary tree, is frequently associated with inflammatory bowel disease, usually chronic ulcerative colitis. Long-term follow-up of patients with PSC has revealed a high incidence of colon cancer and bile duct cancer, both of which are most likely related to the chronic inflammation involving these two organs. Although PSC is an unusual disease, it is now diagnosed with approximately the same frequency as is primary biliary cirrhosis. The histopathologic evolution of PSC results in irreversible damage to bile ducts, which ultimately leads to cholestasis, cirrhosis, liver failure, and premature death from liver failure unless liver transplantation is performed. Therefore, the best chance of achieving success is to treat patients with early-stage disease rather than those with irreversible end-stage cirrhotic disease. Although several medical therapies for PSC have been evaluated, only d-penicillamine, cyclosporine, methotrexate, and, most recently, ursodeoxycholic acid have been studied in controlled clinical trials. Furthermore, several surgical therapies for PSC and its associated complications have been assessed.

      Conclusion

      Currently, no therapy achieves a complete clinical, biochemical, or histologic remission in this disease. Until the etiopathogenesis of PSC is further defined, effective therapy is unlikely to be found. Thus, liver transplantation will continue to be an important therapeutic intervention for the management of patients with end-stage PSC.
      AIDS (acquired immunodeficiency syndrome), ANCAs (anti-neutrophil cytoplasmic antibodies), D3D (irritable bowel disease), p-ANCA (perinuclear ANCA), PSC (primary sclerosing cholangitis), TIPS (transjugular intrahepatic portosystemic shunt)
      Primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease, most commonly occurs in young male patients and is frequently associated with inflammatory bowel disease (IBD) (in 70 to 80% of cases), usually chronic ulcerative colitis.
      • Wiesner RH
      • LaRusso NF
      Clinicopathologic features of the syndrome of primary sclerosing cholangitis.
      • Chapman RW
      • Arborgh BA
      • Rhodes JM
      • Summerfield JA
      • Dick R
      • Scheuer PJ
      • et al.
      Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology.
      • Wiesner RH
      • Porayko MK
      • LaRusso NF
      • Ludwig J
      Primary sclerosing cholangitis.
      It is characterized by fibrosing inflammation of both the intrahepatic and the extrahepatic biliary tree. PSC is diagnosed on the basis of the following criteria: (1) a cholestatic biochemical profile (alkaline phosphatase level, more than 1.5 times the upper limit of normal) for 6 months or more; (2) a cholangiogram that shows strictures, beading, and irregularity of the intrahepatic or the extrahepatic biliary tree (or both) (Fig. 1); and (3) a liver biopsy specimen that reveals inflammatory fibrosis of interlobular and septal bile ducts as well as early evidence of obliteration (Fig. 2) in the absence of evidence of other causes of chronic liver disease. Causes of secondary sclerosing cholangitis, which can occur in association with previous biliary surgical treatments, choledocholithiasis, acquired immunodeficiency syndrome (AIDS), congenital abnormalities of the biliary tree, or intra-arterial infusion of chemotherapeutic agents, must be excluded.
      • Ludwig J
      • LaRusso NF
      • Wiesner RH
      The syndrome of primary sclerosing cholangitis.
      • Ludwig J
      • Kim CH
      • Wiesner RH
      • Krom RAF
      Floxuridine-induced sclerosing cholangitis: an ischemic cholangiopathy?.
      Figure thumbnail gr1
      Fig. 1Endoscopic retrograde cholangiogram, showing classic findings in setting of primary sclerosing cholangitis, including strictures, beading, and irregularities of extrahepatic and intrahepatic biliary system.
      Figure thumbnail gr2
      Fig. 2Photomicrographs of liver biopsy specimens. A, Concentric peribiliary fibrosis and inflammation characteristic of early bile duct damage in setting of primary sclerosing cholangitis. (Hematoxylin-eosin; original magnification, ×300.) B, Concentric peribiliary fibrosis that leads to early obliteration of intralobular bile duct during late stages of primary sclerosing cholangitis. (Hematoxylin-eosin; original magnification, ×250.)
      PSC progresses slowly during a 10- to 15-year period and often leads to biliary fibrosis and cirrhosis, portal hypertension, and premature death from liver failure.
      • Wiesner RH
      • Grambsch PM
      • Dickson ER
      • Ludwig J
      • MacCarty RL
      • Hunter EB
      • et al.
      Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis.
      • Farrant JM
      • Hayllar KM
      • Wilkinson ML
      • Karani J
      • Portmann BC
      • Westaby D
      • et al.
      Natural history and prognostic variables in primary sclerosing cholangitis.
      • Porayko MK
      • LaRusso NF
      • Wiesner RH
      Primary sclerosing cholangitis: a progressive disease?.
      The cause of PSC remains unknown; however, evidence suggests that it is an autoimmune disease associated with immunologic damage directed at bile duct epithelial cells.
      • Chapman RW
      • Jewell DP
      Primary sclerosing cholangitis—an immunologically mediated disease?.
      • Crippin JS
      • Lindor KD
      Primary sclerosing cholangitis: etiology and immunology.
      Patients with PSC commonly have fatigue, pruritus, and jaundice; bacterial cholangitis occurs less often. Recently, however, PSC has been frequently diagnosed during the asymptomatic phase of bacterial cholangitis because of its known association with IBD and because biochemical liver function screening is now part of most general examinations.
      • Sivak Jr, MV
      • Farmer RG
      • Lalli AF
      Sclerosing cholangitis: its increasing frequency of recognition and association with inflammatory bowel disease.
      As PSC progresses and biliary cirrhosis becomes established, various degrees of steatorrhea and fat-soluble vitamin deficiency develop.
      • Wiesner RH
      • Porayko MK
      • LaRusso NF
      • Ludwig J
      Primary sclerosing cholangitis.
      In addition, dominant strictures of major bile ducts can occur, an outcome that can lead to obstruction and sludging of the biliary tree with associated bacterial cholangitis. In patients who have both PSC and biliary cirrhosis, the risk of bile duct cancer developing seems increased.
      • Wee A
      • Ludwig J
      • Coffey Jr, RJ
      • LaRusso NF
      • Wiesner RH
      Hepatobiliary carcinoma associated with primary sclerosing cholangitis and chronic ulcerative colitis.
      • MacCarty RL
      • LaRusso NF
      • May GR
      • Bender CE
      • Wiesner RH
      • King JE
      • et al.
      Cholangiocarcinoma complicating primary sclerosing cholangitis: cholangiographic appearances.
      • Rosen CB
      • Nagorney DM
      • Wiesner RH
      • Coffey Jr, RJ
      • LaRusso NF
      Cholangiocarcinoma complicating primary sclerosing cholangitis.
      • Stieber AC
      • Marino IR
      • Iwatsuki S
      • Starzl TE
      Cholangiocarcinoma in sclerosing cholangitis: the role of liver transplantation.
      • Miros M
      • Kerlin P
      • Walker N
      • Harper J
      • Lynch S
      • Strong R
      Predicting cholangiocarcinoma in patients with primary sclerosing cholangitis before transplantation.
      Although the diagnosis of bile duct cancer is difficult to establish in patients with PSC, this disease should be considered when a patient with long-standing PSC has rapid clinical deterioration. Finally, in patients with biliary cirrhosis who experience complications of portal hypertension, such as esophageal variceal bleeding, ascites, and portal-systemic encephalopathy, a liver transplant should be considered a lifesaving therapeutic option.
      • McEntee G
      • Wiesner RH
      • Rosen C
      • Cooper J
      • Wahlstrom E
      A comparative study of patients undergoing liver transplantation for primary sclerosing cholangitis and primary biliary cirrhosis.
      • Langnas AN
      • Grazi GL
      • Stratta RJ
      • Wood RP
      • Marujo W
      • Markin RS
      • et al.
      Primary sclerosing cholangitis: the emerging role for liver transplantation.

      EPIDEMIOLOGIC FACTORS

      Although the prevalence of PSC in the United States is unknown, it can be estimated because of its frequent association with chronic ulcerative colitis. Studies have shown a 2.4 to 7.5% prevalence of PSC in patients with chronic ulcerative colitis. Because the incidence of chronic ulcerative colitis ranges from 40 to 225 cases per 100,000 population, the incidence of PSC in the United States is estimated to be 2 to 7 cases per 100,000 population.
      • Wiesner RH
      • Porayko MK
      • LaRusso NF
      • Ludwig J
      Primary sclerosing cholangitis.
      This estimate was recently supported by the results of an epidemiologic study from Sweden that noted the incidence of chronic ulcerative colitis and PSC to be 171 and 6.3 cases per 100,000 population, respectively.
      • Olsson R
      • Danielsson A
      • Jarnerot G
      • Lindstrom E
      • Loof L
      • Rolny P
      • et al.
      Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis.
      These results, however, probably underestimate the actual incidence of PSC inasmuch as the disease can occur in patients with normal serum levels of alkaline phosphatase, and 20 to 30% of patients with PSC have no associated IBD. Therefore, PSC seems to be more common than previously suspected and may have a frequency similar to that reported for primary biliary cirrhosis.

      ETIOPATHOGENESIS

      Several mechanisms related to toxins, infections, genetic predisposition, and immunologic abnormalities have been postulated to contribute to the pathogenesis or progression of PSC (Table 1). Each of these proposed pathologic hypotheses will be reviewed in the subsequent sections.
      Table 1Potential Etiopathologic Factors in Primary Sclerosing Cholangitis
      • Portal bacteremia
      • Absorbed colon toxins
      • Toxic bile acids
      • Copper toxicity
      • Viral infection
      • Genetic predisposition
      • Immunologic mechanisms
      • Ischemic arteriolar injury

      Bacteria-Toxin Theory.

      Chronic ulcerative colitis occurs in 70 to 80% of patients at some time during the course of PSC
      • Fausa O
      • Schrumpf E
      • Elgjo K
      Relationship of inflammatory bowel disease and primary sclerosing cholangitis.
      and has been shown to be an indicator of poor prognosis.
      • Wiesner RH
      • Grambsch PM
      • Dickson ER
      • Ludwig J
      • MacCarty RL
      • Hunter EB
      • et al.
      Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis.
      Furthermore, several investigators have suggested that PSC may increase the risk of colon cancer in patients with chronic ulcerative colitis.
      • D'Haens GR
      • Laschner BA
      • Hanauer SB
      Pericholangitis and sclerosing cholangitis are risk factors for dysplasia and cancer in ulcerative colitis.
      • Broome U
      • Lindberg G
      • Lofberg R
      Primary sclerosing cholangitis in ulcerative colitis—a risk factor for the development of dysplasia and DNA aneuploidy?.
      This close association of IBD with PSC has been intriguing and has led several investigators to postulate that portal bacteremia or absorption of toxins or toxic bile acids from the inflamed colon may have a major role in the pathogenesis of PSC.
      • Eade MM
      • Brooke BN
      Portal bacteraemia in cases of ulcerative colitis submitted to colectomy.
      • Palmer KR
      • Duerden BI
      • Holdsworth CD
      Bacteriological and endotoxin studies in cases of ulcerative colitis submitted to surgery.
      • Hobson CH
      • Butt TJ
      • Ferry DM
      • Hunter J
      • Chadwick VS
      • Broom MF
      Enterohepatic circulation of bacterial chemo-tactic peptide in rats with experimental colitis.
      • Holzbach RT
      • March ME
      • Freedman MR
      • Fazio VW
      • Lavery I
      • Jagelman DA
      Portal vein bile acids in patients with severe inflammatory bowel disease.
      Warren and associates
      • Warren KW
      • Athanassiades S
      • Monge JI
      Primary sclerosing cholangitis: a study of forty-two cases.
      were the first investigators to hypothesize that the primary event in PSC was chronic, low-grade portal vein bacteremia, which caused chronic biliary tract inflammation and fibrosis. Other investigators, however, were unable to demonstrate a significant incidence of portal vein bacteremia in patients undergoing an operation for severe, uncontrolled ulcerative colitis.
      • Eade MM
      • Brooke BN
      Portal bacteraemia in cases of ulcerative colitis submitted to colectomy.
      Furthermore, detailed hepatic histologic analysis revealed that portal phlebitis, the hallmark of portal vein bacteremia, was mild or absent in most patients with PSC.
      • Ludwig J
      • Barham SS
      • LaRusso NF
      • Elveback LR
      • Wiesner RH
      • McCall JT
      Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis.
      Thus, evidence to support the hypothesis that portal bacteremia has a major pathogenic role in this syndrome is scarce.
      Some investigators have postulated that PSC is caused by a reaction of toxic bile acids, such as lithocholic acid, arising from the bacterial activity in the diseased colon that allows absorption of the toxin directly into the portal blood.
      • Holzbach RT
      • March ME
      • Freedman MR
      • Fazio VW
      • Lavery I
      • Jagelman DA
      Portal vein bile acids in patients with severe inflammatory bowel disease.
      • Warren KW
      • Athanassiades S
      • Monge JI
      Primary sclerosing cholangitis: a study of forty-two cases.
      This hypothesis has been refuted because some studies have been unable to demonstrate major abnormalities in bile acid metabolism in patients with PSC or with chronic ulcerative colitis.
      • Siegel JH
      • Barnes S
      • Morris JS
      Bile acids in liver disease associated with inflammatory bowel disease.
      Recent studies have reported that a pro-inflammatory bacterial peptide synthesized by colonic bacteria in a rat model may cause portal inflammation and neutrophilic cholangitis similar to the histopathologic lesions noted during the early stages of PSC.
      • Hobson CH
      • Butt TJ
      • Ferry DM
      • Hunter J
      • Chadwick VS
      • Broom MF
      Enterohepatic circulation of bacterial chemo-tactic peptide in rats with experimental colitis.
      In particular, studies have shown that N-formylated chemotactic peptides cause fibrosis and damage to major bile ducts. In one study, animals in which colitis was experimentally induced experienced an eightfold increase in biliary excretion of these pro-inflammatory bacterial peptides.
      • Hobson CH
      • Butt TJ
      • Ferry DM
      • Hunter J
      • Chadwick VS
      • Broom MF
      Enterohepatic circulation of bacterial chemo-tactic peptide in rats with experimental colitis.
      Another study showed that intestinal bacterial overgrowth in rats is associated with hepatic inflammation similar to that observed in PSC.
      • Lichtman SN
      • Sartor RB
      • Keku J
      • Schwab JH
      Hepatic inflammation in rats with experimental small intestinal bacterial overgrowth.
      Thus, further investigation of the potential pathogenic role of proinflammatory bacterial peptides in the etiopathogenesis of PSC seems warranted.
      In contrast, certain evidence suggests that increased absorption of toxins through the inflamed colon has no major part in the etiopathogenesis of PSC. This possibility is supported by the observation that the severity of ulcerative colitis seems not to be related to the risk of PSC developing because most patients with PSC have mild or quiescent IBD.
      • Steckman M
      • Drossman DA
      • Lesesne HR
      Hepatobiliary disease that precedes ulcerative colitis.
      • Schrumpf E
      • Fausa O
      • Kolmannskog F
      • Elgjo K
      • Ritland S
      • Gjone E
      Sclerosing cholangitis in ulcerative colitis: a follow-up study.
      • Stockbrugger RW
      • Olsson R
      • Jaup B
      • Jensen J
      Forty-six patients with primary sclerosing cholangitis: radiological bile duct changes in relationship to clinical course and concomitant inflammatory bowel disease.
      • Cangemi JR
      • Wiesner RH
      • Beaver SJ
      • Ludwig J
      • MacCarty RL
      • Dozois RR
      • et al.
      Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing cholangitis.
      PSC has been known to develop years before the onset of chronic ulcerative colitis, and PSC may also develop years after proctocolectomy for chronic ulcerative colitis. Indeed, my colleagues and I have noted the development of IBD in liver transplant recipients who had PSC years after transplantation. Furthermore, PSC is diagnosed in a substantial number of patients who have no past or present clinical or histologic evidence of ulcerative colitis. These findings suggest that colonic disease associated with increased absorption of bacterial products or toxins may not be a major factor in the pathogenesis of PSC.
      The last toxin worthy of notation relative to the pathogenesis of PSC is copper. We, and others, have shown that PSC leads to an excess accumulation of hepatic copper, which has been postulated to be toxic to hepatocytes.
      • Gross Jr, JR
      • Ludwig J
      • Wiesner RH
      • McCall JT
      • LaRusso NF
      Abnormalities in tests of copper metabolism in primary sclerosing cholangitis.
      In PSC, however, this situation most likely represents a secondary phenomenon related to cholestasis, inasmuch as increased hepatic copper levels are found in all patients with chronic cholestasis regardless of the cause. Therefore, the pathogenesis of PSC is unlikely to be related to a primary defect in copper metabolism. Furthermore, in a controlled clinical trial, d-penicillamine therapy, which is known to be associated with decreasing hepatic copper levels, was not shown to have a beneficial effect on PSC.
      • LaRusso NF
      • Wiesner RH
      • Ludwig J
      • MacCarty RL
      • Beaver SJ
      • Zinsmeister AR
      Prospective trial of penicillamine in primary sclerosing cholangitis.
      Therefore, evidence to support hepatic copper toxicity as a major factor in the etiopathogenesis or the progression of PSC is scarce.

      Viral Infections.

      Infection of biliary epithelial cells by viral agents has been postulated by some investigators to be involved in the pathogenesis of PSC. The results of several studies have essentially excluded hepatitis A, B, C, and D as etiologic factors in PSC.
      • Wiesner RH
      • Porayko MK
      • LaRusso NF
      • Ludwig J
      Primary sclerosing cholangitis.
      Cytomegalovirus infection has been implicated in the etiopathogenesis of PSC. Because this infection can cause interlobular bile duct damage, it has been implicated in decreasing the number of interlobular bile ducts;
      • Finegold MJ
      • Carpenter RJ
      Obliterative cholangitis due to cytomegalovirus: a possible precursor of paucity of intrahepatic bile ducts.
      however, fibrosis, obliterative cholangitis, and destruction of large bile ducts have never been shown conclusively to be associated with cytomegalovirus infection. More important, inclusion bodies, typical of cytomegalovirus infection, have never been demonstrated histologically in bile duct epithelial cells or in the hepatocytes of patients with PSC.
      • Ludwig J
      • Barham SS
      • LaRusso NF
      • Elveback LR
      • Wiesner RH
      • McCall JT
      Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis.
      Finally, with use of a sensitive polymerase chain reaction-based assay, analysis of liver tissue from patients with PSC detected human cytomegalovirus DNA in only 1 of 37 patients; thus, any pronounced human cytomegalovirus reactivation in these tissues was excluded, an outcome that suggests that human cytomegalovirus replication and reactivation are not responsible for the cause or the progression of the disease.
      • Mehal WZ
      • Hattersley AT
      • Chapman RW
      • Fleming KA
      A survey of cytomegalovirus (CMV) DNA in primary sclerosing cholangitis (PSC) liver tissues using a sensitive polymerase chain reaction (PCR) based assay.
      Reports that suggest that reovirus type 3 can induce cholangitis and biliary atresia in weanling mice and primates have raised the possibility that this virus may also be an etiologic factor in PSC.
      • Phillips PA
      • Keast D
      • Papadimitriou JM
      • Walters MN
      • Stanley NF
      Chronic obstructive jaundice induced by reovirus type 3 in weanling mice.
      • Morecki R
      • Glaser JH
      • Cho S
      • Balistreri WF
      • Horwitz MS
      Biliary atresia and reovirus type 3 infection.
      More recent data, however, have shown that neither the prevalence nor the titers of antibodies to this virus differ between normal adult control patients and patients with PSC.
      • Minuk GY
      • Rascanin N
      • Paul RW
      • Lee PW
      • Buchan K
      • Kelly JK
      Reovirus type 3 infection in patients with primary biliary cirrhosis and primary sclerosing cholangitis.
      Thus, currently, no conclusive evidence supports the hypothesis that the etiopathogenesis of PSC is related to a viral infection. Nonetheless, a viral infection in which immunologic determinants are altered has yet to be excluded as a pathogenic factor.

      Genetic Predisposition.

      During the past several years, it has become evident that genetic factors may have an important role in PSC. Findings to support this statement include the fact that several HLA molecules, including HLA-B8, HLA-DR2, HLA-DR3, and HLA-DRw5s2A, have been found to be associated with PSC.
      • Chapman RW
      • Varghese Z
      • Gaul R
      • Patel G
      • Kokinon N
      • Sherlock S
      Association of primary sclerosing cholangitis with HLA-B8.
      • Donaldson PT
      • Farrant JM
      • Wilkinson ML
      • Hay liar K
      • Portmann BC
      • Williams R
      Dual association of HLA DR2 and DR3 with primary sclerosing cholangitis.
      • Prochazka EJ
      • Terasaki PI
      • Park MS
      • Goldstein LI
      • Busuttil RW
      Association of primary sclerosing cholangitis with HLA-DRw52a.
      The finding of HLA-DRw52A in 100% of white North American patients with PSC
      • Prochazka EJ
      • Terasaki PI
      • Park MS
      • Goldstein LI
      • Busuttil RW
      Association of primary sclerosing cholangitis with HLA-DRw52a.
      was not confirmed, however, in a group of Swedish patients in whom a more specific assay was used.
      • Zetterquist H
      • Broome U
      • Einarsson K
      • Olerup O
      HLA class II genes in primary sclerosing cholangitis and chronic inflammatory bowel disease: no HLA-DRw52a association in Swedish patients with sclerosing cholangitis.
      Farrant and colleagues
      • Farrant JM
      • Doherty DG
      • Donaldson PT
      • Vaughan RW
      • Hayllar KM
      • Welsh Kl
      • et al.
      Amino acid substitutions at position 38 of the DR beta polypeptide confer susceptibility to and protection from primary sclerosing cholangitis.
      analyzed the frequency of the DRB3*0101 allele, which encodes HLA-DRw52A in patients with PSC; indeed, this was the most strongly associated allele present in 55% of patients with PSC but was also present in 22% of control subjects.
      Furthermore, familial occurrence of PSC has been reported by several investigators.
      • Jorge AD
      • Esley C
      • Ahumada J
      Family incidence of primary sclerosing cholangitis associated with immunologic diseases.
      • Quigley EM
      • LaRusso NF
      • Ludwig J
      • MacSween RN
      • Birnie GG
      • Watkinson G
      Familial occurrence of primary sclerosing cholangitis and ulcerative colitis.
      Some studies have indicated a strong relationship between PSC and HLA haplotypes B8 and DR3, both of which are known to be associated with other autoimmune diseases. Other studies have found that the HLA haplotype DR2, in addition to B8 and DR3, is an independent factor that seems to influence the initiation of PSC.
      • Donaldson PT
      • Farrant JM
      • Wilkinson ML
      • Hay liar K
      • Portmann BC
      • Williams R
      Dual association of HLA DR2 and DR3 with primary sclerosing cholangitis.
      Of interest, DR3-positive patients had PSC diagnosed at a significantly younger age than did those who were DR2 positive. Further studies are needed to correlate immunologic abnormalities that are found in association with these HLA haplotypes in patients with PSC and to evaluate their relationship to the cause of PSC.

      Immunologic Causes.

      Although the evidence is currently inconclusive, immunologic damage to the biliary tree remains the most attractive cause of PSC.
      • Chapman RW
      • Jewell DP
      Primary sclerosing cholangitis—an immunologically mediated disease?.
      • Crippin JS
      • Lindor KD
      Primary sclerosing cholangitis: etiology and immunology.
      Like primary biliary cirrhosis (which is thought to be a model autoimmune disease), PSC is characterized by lymphocytic infiltration and bile duct destruction; hypergammaglobulinemia, often in conjunction with a disproportionate increase in serum IgM levels; and an association with other autoimmune disorders such as IBD, thyroiditis, and arthritis.
      • Wiesner RH
      • LaRusso NF
      • Ludwig J
      • Dickson ER
      Comparison of the clinicopathologic features of primary sclerosing cholangitis and primary biliary cirrhosis.
      Nonetheless, classic autoantibodies, such as antimitochondrial antibody, anti-nuclear antibody, and anti-smooth muscle antibody, seem to be present with less frequency in PSC than in primary biliary cirrhosis.
      • Chapman RW
      • Cottone M
      • Selby WS
      • Shepherd HA
      • Sherlock S
      • Jewell DP
      Serum autoantibodies, ulcerative colitis and primary sclerosing cholangitis.
      Recent studies of PSC have found a high incidence of circulating anticolon antibodies, anti-neutrophil nuclear antibodies, and anti-neutrophil cytoplasmic antibodies (ANCAs).
      • Snook JA
      • Chapman RW
      • Fleming K
      • Jewell DP
      Anti-neutrophil nuclear antibody in ulcerative colitis, Crohn's disease and primary sclerosing cholangitis.
      • Duerr RH
      • Targan SR
      • Landers CJ
      • LaRusso NF
      • Lindsay KL
      • Wiesner RH
      • et al.
      Neutrophil cytoplasmic antibodies: a link between primary sclerosing cholangitis and ulcerative colitis.
      • Das KM
      • Vecchi M
      • Sakamaki S
      A shared and unique epitope(s) on human colon, skin, and biliary epithelium detected by a monoclonal antibody.
      • Lo SK
      • Fleming KA
      • Chapman RW
      Prevalence of anti-neutrophil antibody in primary sclerosing cholangitis and ulcerative colitis using an alkaline phosphatase technique.
      • Klein R
      • Eisenburg J
      • Weber P
      • Seibold F
      • Berg PA
      Significance and specificity of antibodies to neutrophils detected by Western blotting for the serological diagnosis of primary sclerosing cholangitis.
      • Seibold F
      • Weber P
      • Klein R
      • Berg PA
      • Wiedmann KH
      Clinical significance of antibodies against neutrophils in patients with inflammatory bowel disease and primary sclerosing cholangitis.
      • Halbwachs-Mecarelli L
      • Nusbaum P
      • Noel LH
      • Reumaux D
      • Erlinger S
      • Grunfeld JP
      • et al.
      Antineutrophil cytoplasmic antibodies (ANCA) directed against cathepsin G in ulcerative colitis, Crohn's disease and primary sclerosing cholangitis.
      Indeed, anti-neutrophil nuclear antibodies have been isolated in 84% of patients with PSC and in 86% with IBD. Anti-neutrophil cytoplasmic antibodies have been demonstrated in 79% of patients with chronic ulcerative colitis, in 82% with PSC, and in 79% with PSC and chronic ulcerative colitis. Although 63% of liver disease control sera tested positive in the fixed neutrophil enzyme-linked immunosorbent assay, the levels of binding were significantly less for all liver diseases tested in comparison with PSC. Thus, the current data strongly support the thesis that, in patients with ulcerative colitis and PSC, perinuclear ANCA (p-ANCA) reactive antigens are similar and may be indicative of a common immunopathologic mechanism. Indeed, the following similarities have been observed. (1) Sera from both diseases yield a perinuclear immunofluorescent staining pattern with alcohol-fixed neutrophils. (2) No correlation exists between disease activity and p-ANCA. (3) In both PSC and ulcerative colitis, p-ANCAs are specific for neutrophils. (4) No reaction has been noted with any protein antigen implicated in other chronic inflammatory conditions. Unfortunately (as with other autoimmune markers), whether these antibodies are of diagnostic or prognostic importance is unclear, and the proteinaceous antigen to which these antibodies react remains undefined. Finally, whether these findings represent a clue to the etiopathogenesis of PSC or whether they represent an epiphenomenon related to chronic liver disease is unknown. Further detailed studies are needed for a precise definition of the role of ANCAs and their association with PSC.
      Other evidence supportive of the hypothesis that the humoral immune system may have a role in the pathogenesis of PSC was reported by Bodenheimer and coworkers,
      • Bodenheimer Jr, HC
      • LaRusso NF
      • Thayer Jr, WR
      • Charland C
      • Staples PJ
      • Ludwig J
      Elevated circulating immune complexes in primary sclerosing cholangitis.
      who found circulating immune complexes in more than 80% of patients with PSC. In addition, immune complexes have been noted in the bile of patients with PSC.
      • Alberti-Flor JJ
      • de Medina M
      • Jeffers L
      • Schiff ER
      Elevated immunoglobulins and immune complexes in the bile of patients with primary sclerosing cholangitis [abstract].
      Although serum and bile immune complexes are insufficient evidence to establish a pathogenic role, further studies are warranted to characterize the antigen and antibody components of these immune complexes.
      Additional studies that support humoral immunologic causes for PSC showed evidence of increased catabolism of complement C3, increased activation of the complement system, and abnormal clearance of the immune complexes from the circulation of patients with PSC, findings that suggest dysfunction of reticuloendothelial activity.
      • Brinch L
      • Teisberg P
      • Schrumpf E
      • Akesson I
      The in vivo metabolism of C3 in hepatobiliary disease associated with ulcerative colitis.
      • Senaldi G
      • Donaldson PT
      • Magrin S
      • Farrant JM
      • Alexander GJ
      • Vergani D
      • et al.
      Activation of the complement system in primary sclerosing cholangitis.
      • Minuk GY
      • Angus M
      • Brickman CM
      • Lawley TJ
      • Frank MM
      • Hoofnagle JH
      • et al.
      Abnormal clearance of immune complexes from the circulation of patients with primary sclerosing cholangitis.
      Although these findings support the hypothesis that the cause of PSC may be related to circulating immune complexes in association with activation of complement, whether these are primary or secondary events related to the liver disease process itself is unknown.
      In addition to the abnormalities found in the humoral immune system in patients with PSC, increased numbers of abnormalities have been found in the cellular immune system. Several studies have reported a significant decrease in the total number of circulating T cells in patients with PSC in comparison with a normal control population because of a disproportionate decrease in CD8 cells (cytotoxic cells), which leads to a significant increase in the CD4/CD8 ratio.
      • Lindor KD
      • Wiesner RH
      • Katzmann JA
      • LaRusso NF
      • Beaver SJ
      Lymphocyte subsets in primary sclerosing Cholangitis.
      • Snook JA
      • Chapman RW
      • Sachdev GK
      • Heryet A
      • Kelly PM
      • Fleming KA
      • et al.
      Peripheral blood and portal tract lymphocyte populations in primary sclerosing cholangitis.
      • Chapman RW
      • Kelly PM
      • Heryet A
      • Jewell DP
      • Fleming KA
      Expression of HLA-DR antigens on bile duct epithelium in primary sclerosing cholangitis.
      One study found that patients with PSC and cirrhosis had a further significant increase in the CD4/CD8 ratio in comparison with patients who had no cirrhosis.
      • Lindor KD
      • Wiesner RH
      • Katzmann JA
      • LaRusso NF
      • Beaver SJ
      Lymphocyte subsets in primary sclerosing Cholangitis.
      In other studies, the demonstration of enhanced expression of class II antigens on biliary epithelial cells during the early stages of the disease suggests that biliary epithelial cells may manifest self-antigens to host lymphocytes.
      • Chapman RW
      • Kelly PM
      • Heryet A
      • Jewell DP
      • Fleming KA
      Expression of HLA-DR antigens on bile duct epithelium in primary sclerosing cholangitis.
      • Broome U
      • Glaumann H
      • Hultcrantz R
      • Forsum U
      Distribution of HLA-DR, HLA-DP, HLA-DQ antigens in liver tissue from patients with primary sclerosing cholangitis.
      McFarlane and colleagues
      • McFarlane IG
      • Wojcicka BM
      • Tsantoulas DC
      • Portmann BC
      • Eddleston AL
      • Williams R
      Leukocyte migration inhibition in response to biliary antigens in primary biliary cirrhosis, sclerosing cholangitis, and other chronic liver diseases.
      demonstrated inhibition of leukocyte migration by biliary antigens, and others have shown enhanced autoreactivity of T lymphocytes in patients with PSC.
      • Lindor KD
      • Wiesner RH
      • LaRusso NF
      • Homburger HA
      Enhanced autoreactivity of T-lymphocytes in primary sclerosing Cholangitis.
      Finally, studies of inflammatory cells that infiltrate the portal tracts of patients with PSC have demonstrated the presence of both CD4 and CD8 cells, and an increased proportion of CD8 cells has been found in areas of bile duct proliferation and infiltration of bile duct epithelium.
      • Snook JA
      • Chapman RW
      • Sachdev GK
      • Heryet A
      • Kelly PM
      • Fleming KA
      • et al.
      Peripheral blood and portal tract lymphocyte populations in primary sclerosing cholangitis.
      These findings suggest that biliary epithelial cells are indeed targets of the immune response in PSC. Further studies are needed, however, to confirm these findings and to determine which immunologic abnormalities are primary events and of etiologic importance and which are merely secondary events related to progressive bile duct arteriolar injury.

      Ischemic Arteriolar Injury.

      Direct injury to the peribiliary arteriolar plexus can result in injury to and necrosis of bile ducts. This situation has been demonstrated most clearly in patients who have received intra-arteriolar infusions of floxuridine, which can produce diffuse obliterative thromboendarteritis of feeder vessels and lead to focal strictures in the extrahepatic and intrahepatic bile ducts, findings that are indistinguishable from PSC.
      • Ludwig J
      • Kim CH
      • Wiesner RH
      • Krom RAF
      Floxuridine-induced sclerosing cholangitis: an ischemic cholangiopathy?.
      Similar features can be noted in patients with polyarteritis nodosa and in those with hepatic artery thrombosis associated with liver transplantation. Although one is tempted to speculate that peribiliary arteriolar injury may be the cause of PSC, thorough histologic analysis of the recipient bile ducts, peribiliary arterioles, and arteries in patients with PSC undergoing liver transplantation has failed to reveal evidence of vascular injury.
      • Ludwig J
      • LaRusso NF
      • Wiesner RH
      The syndrome of primary sclerosing cholangitis.
      In summary, the cause of PSC remains poorly defined; however, several factors suggest an immunologic component to the pathogenesis of the disease. Abnormalities in both the humoral and the cell-mediated immunologic processes, as well as the aberrant expression of class II HLA antigens on biliary epithelial cells, strongly suggest an immunologically mediated disease. Unfortunately, no hypothesis exists that can explain the pathologic findings, the association with ulcerative colitis in most patients with PSC, or the observations of disturbed immunologic function. Further studies are needed to determine the importance of the previously mentioned findings. Moreover, an understanding of the immunologic mechanisms associated with bile duct injury in patients with PSC as well as identification of the antigens to which the immunologic attack is directed is essential not only for determining the etiopathogenesis of PSC but also for guiding efforts in the development of effective therapy.

      NATURAL HISTORY

      On the basis of several recent prospective studies, evidence shows that PSC is frequently a progressive disease. The largest of these studies from the Mayo Clime involved 174 patients with PSC; the mean follow-up was 6 years.
      • Wiesner RH
      • Grambsch PM
      • Dickson ER
      • Ludwig J
      • MacCarty RL
      • Hunter EB
      • et al.
      Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis.
      The median survival from the time of diagnosis of PSC was 11.9 years, and both symptomatic and asymptomatic patients had a shorter survival period than did a US population matched for age, sex, and race (Fig. 3). These findings have been confirmed by several other centers that have reported the median survival from the time of diagnosis of PSC to be between 9 and 11 years.
      • Farrant JM
      • Hayllar KM
      • Wilkinson ML
      • Karani J
      • Portmann BC
      • Westaby D
      • et al.
      Natural history and prognostic variables in primary sclerosing cholangitis.
      • Heizberg JH
      • Petersen JM
      • Boyer JL
      Improved survival with primary sclerosing cholangitis: a review of clinicopathologic features and comparison of symptomatic and asymptomatic patients.
      • Aadland E
      • Schrumpf E
      • Fausa O
      • Elgjo K
      • Heilo A
      • Aakhus T
      • et al.
      Primary sclerosing cholangitis: a long-term follow-up study.
      • Dickson ER
      • Murtaugh PA
      • Wiesner RH
      • Grambsch PM
      • Fleming TR
      • Ludwig J
      • et al.
      Primary sclerosing cholangitis: refinement and validation of survival models.
      • Porayko MK
      • Wiesner RH
      • LaRusso NF
      • Ludwig J
      • MacCarty RL
      • Steiner BL
      • et al.
      Patients with asymptomatic primary sclerosing cholangitis frequently have progressive disease.
      Figure thumbnail gr3
      Fig. 3Kaplan-Meier estimated survival curves for asymptomatic and symptomatic patients with primary sclerosing cholangitis. For comparison, survival curves in US population matched for age, sex, and race to asymptomatic patients are also shown. Difference in survival: asymptomatic versus control subjects, P<0.001; symptomatic versus asymptomatic patients, P<0.003.
      (From Wiesner and associates.
      • Wiesner RH
      • Grambsch PM
      • Dickson ER
      • Ludwig J
      • MacCarty RL
      • Hunter EB
      • et al.
      Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis.
      By permission of Mosby-Year Book.)
      A subgroup of patients with PSC who had no symptoms at the time of diagnosis has also been monitored prospectively. At the Mayo Clinic, 45 patients with PSC but with no symptoms related to liver disease were followed up for a mean of 6.25 years.
      • Porayko MK
      • Wiesner RH
      • LaRusso NF
      • Ludwig J
      • MacCarty RL
      • Steiner BL
      • et al.
      Patients with asymptomatic primary sclerosing cholangitis frequently have progressive disease.
      During this follow-up period, 76% experienced progression of liver disease based on clinical and pathologic findings, and in 31%, liver failure developed, a situation that resulted in death or in the need for lifesaving liver transplantation.
      In contrast, however, some institutions have found PSC to be more benign. In a retrospective study with short-term follow-up, Yale investigators reported an overall 75% 9-year survival rate.
      • Heizberg JH
      • Petersen JM
      • Boyer JL
      Improved survival with primary sclerosing cholangitis: a review of clinicopathologic features and comparison of symptomatic and asymptomatic patients.
      Furthermore, studies from Norway estimated the mean survival of patients with PSC to be 17 years after the initial diagnosis.
      • Aadland E
      • Schrumpf E
      • Fausa O
      • Elgjo K
      • Heilo A
      • Aakhus T
      • et al.
      Primary sclerosing cholangitis: a long-term follow-up study.
      Reasons for these differences have recently been put into perspective.
      • Porayko MK
      • LaRusso NF
      • Wiesner RH
      Primary sclerosing cholangitis: a progressive disease?.
      First, PSC progresses silently for several years and can be detected only by prospective follow-up with liver function tests and hepatic histologic examinations, studies that were not done in several of the reported articles. Second, early detection of the disease is associated with prolonged survival, an outcome that seems to have eventuated in the Norwegian studies, in which patients with IBD who had minimal abnormalities on liver function tests were aggressively assessed with cholangiography.
      • Aadland E
      • Schrumpf E
      • Fausa O
      • Elgjo K
      • Heilo A
      • Aakhus T
      • et al.
      Primary sclerosing cholangitis: a long-term follow-up study.
      Third, the beginning point for survival analysis is important for determining the overall survival time. The comparison of one group of patients in whom follow-up began at the time of cholangiographic diagnosis of PSC with a second group of patients in whom the diagnosis of PSC was backdated to the time of the first onset of symptoms or biochemical abnormalities would provide different survival times. Therefore, if these differences in study design are taken into account, the weight of evidence indicates that PSC in most patients is, indeed, a progressive disease.
      That PSC evolves into a ductopenic syndrome in which progressive stricture of large and small bile ducts occurs is known. The overall result is that interlobular and septal bile ducts become obliterated and functionally lost. In the histopathologic evolution of PSC (Fig. 4), when a critical number of interlobular and septal bile ducts are lost, cholestasis occurs and leads to early portal fibrosis and, eventually, to irreversible biliary cirrhosis. Thus, therapeutic intervention is most successful when it is instituted early during the course of the disease before irreversible damage occurs.
      Figure thumbnail gr4
      Fig. 4Graph depicting histopathologic evolution of primary sclerosing cholangitis from reversible stage, during which early bile duct damage occurs and which should respond to medical therapy, to irreversible fibrotic-cirrhotic stage, which is resistant to medical intervention.

      PROGNOSTIC SURVIVAL MODELS

      Two major purposes for establishing the natural history of PSC are to determine an accurate rate of disease progression and to estimate survival for an individual patient at any specific time during the course of PSC. Predicting survival on the basis of clinical, biochemical, and histologic features of PSC is important for timing liver transplantation and for monitoring therapeutic intervention. The use of sophisticated statistical approaches—most notably, the Cox multivariate regression analysis—has facilitated the development of a prognostic model based on five independent variables in which a survival risk score can be calculated and translated into a survival function for estimating survival for an individual patient with PSC.
      • Wiesner RH
      • Grambsch PM
      • Dickson ER
      • Ludwig J
      • MacCarty RL
      • Hunter EB
      • et al.
      Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis.
      Indeed, we and others have developed several such models based on long-term follow-up of a large group of patients with PSC in whom important clinical predictors of prognosis were determined.
      • Wiesner RH
      • Grambsch PM
      • Dickson ER
      • Ludwig J
      • MacCarty RL
      • Hunter EB
      • et al.
      Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis.
      • Farrant JM
      • Hayllar KM
      • Wilkinson ML
      • Karani J
      • Portmann BC
      • Westaby D
      • et al.
      Natural history and prognostic variables in primary sclerosing cholangitis.
      In one model, patient age, serum bilirubin level, hemoglobin concentration, hepatic histologic stage, and presence or absence of IBD were identified as independent prognostic variables.
      • Wiesner RH
      • Grambsch PM
      • Dickson ER
      • Ludwig J
      • MacCarty RL
      • Hunter EB
      • et al.
      Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis.
      In another model, on the basis of data from five major liver centers throughout the world, serum bilirubin level, histologic stage, patient age, and splenomegaly were identified as significant prognostic variables.
      • Dickson ER
      • Murtaugh PA
      • Wiesner RH
      • Grambsch PM
      • Fleming TR
      • Ludwig J
      • et al.
      Primary sclerosing cholangitis: refinement and validation of survival models.
      With use of these models, liver transplantation has been shown to prolong survival significantly in patients with end-stage PSC in comparison with estimated survival without liver transplantation (Fig. 5).
      • Abu-Elmagd KM
      • Malinchoc M
      • Dickson ER
      • Fung JJ
      • Murtaugh PA
      • Langworthy AL
      • et al.
      Efficacy of hepatic transplantation in patients with primary sclerosing cholangitis.
      Of importance, these models have not been evaluated prospectively and have not been cross-validated; thus, their applicability to the complete spectrum of patients with PSC remains unproved at this time. Additional studies are under way to test their application for timing liver transplantation, to refine these models further, and to evaluate their usefulness in monitoring the effect of experimental therapy on disease progression.
      Figure thumbnail gr5
      Fig. 5Estimated survival (based on Kaplan-Meier analysis) after liver transplantation in patients with primary sclerosing cholangitis (PSC) and estimated survival without liver transplantation as predicted by Mayo Clinic survival model. Liver transplantation increases survival significantly in patients with end-stage PSC.
      (Modified from Abu-Elmagd and associates.
      • Abu-Elmagd KM
      • Malinchoc M
      • Dickson ER
      • Fung JJ
      • Murtaugh PA
      • Langworthy AL
      • et al.
      Efficacy of hepatic transplantation in patients with primary sclerosing cholangitis.
      By permission of Surgery, Gynecology & Obstetrics.)

      TREATMENT

      Treatment of PSC can be classified into five major categories: (1) specific therapy for disrupting disease progression, (2) management of complications of chronic cholestasis, (3) management of complications of portal hypertension, (4) therapy for complications specific to PSC, and (5) liver transplantation.

      Specific Therapy for Halting Disease Progression.

      Medical therapy for PSC has witnessed the evolution of several diverse agents, which attests to the lack of understanding of the etiopathogenesis of this disease (Table 2).
      Table 2Medical Treatment That Has Been Evaluated for Primary Sclerosing Cholangitis
      • d-Penicillamine
        Evaluated in controlled trials.
      • Cyclosporine
        Evaluated in controlled trials.
      • Methotrexate
        Evaluated in controlled trials.
      • Ursodeoxycholic acid
        Evaluated in controlled trials.
      • Corticosteroids
      • Azathioprine
      • Colchicine
      • Cholestyramine
      • Antibiotics
      * Evaluated in controlled trials.

      d-Penicillamine.

      Finding increased hepatic copper levels in patients with PSC provided the major rationale for evaluating d-penicillamine therapy in a controlled clinical trial. In a Mayo Clinic study, 70 patients with PSC randomly received either d-penicillamine or placebo. At 36-month follow-up, d-penicillamine showed no beneficial effect on disease progression, on the basis of clinical, biochemical, radiologic, histologic, and survival data. In addition, major side effects occurred in 21% of patients who received this agent.
      • LaRusso NF
      • Wiesner RH
      • Ludwig J
      • MacCarty RL
      • Beaver SJ
      • Zinsmeister AR
      Prospective trial of penicillamine in primary sclerosing cholangitis.

      Corticosteroids.

      Both topically applied and systemic modes of corticosteroid therapy have been evaluated in patients with PSC.
      • Allison MC
      • Burroughs AK
      • Noone P
      • Summerfield JA
      Biliary lavage with corticosteroids in primary sclerosing cholangitis: a clinical, cholangiographic and bacteriological study.
      • Burgert SL
      • Brown BP
      • Kirkpatrick RB
      • LaBrecque DR
      Positive corticosteroid response in early primary sclerosing cholangitis [abstract].
      Most studies have been unable to confirm a long-term beneficial effect with corticosteroid therapy in such patients. Furthermore, corticosteroid therapy for PSC has been associated with enhanced loss of trabecular bone, a situation that leads to an increased risk of the development of osteoporosis and compression fractures of the spine.

      Cyclosporine.

      Cyclosporine therapy was evaluated in a controlled clinical trial that involved a few patients.
      • Wiesner RH
      • Steiner B
      • LaRusso NF
      • Lindor KD
      • Baldus WP
      A controlled clinical trial evaluating cyclosporine in the treatment of primary sclerosing cholangitis [abstract].
      Although it has been shown to be beneficial for patients with primary biliary cirrhosis and chronic ulcerative colitis, my colleagues and I have noted only a biochemical improvement in our patients with PSC. In particular, we found a substantial decrease in serum levels of alkaline phosphatase; however, we were unable to demonstrate an effect on cholestatic symptoms, prevention of histologic progression, or progression to complications of portal hypertension. Therefore, the results of cyclosporine therapy, to date, have been disappointing.

      Methotrexate.

      Methotrexate was evaluated in the treatment of PSC in a double-blind controlled trial.
      • Knox TA
      • Kaplan MM
      Treatment of primary sclerosing cholangitis with oral methotrexate.
      • Knox TA
      • Kaplan MM
      A double-blind controlled trial of oral-pulse methotrexate therapy in the treatment of primary sclerosing cholangitis.
      It decreased serum levels of alkaline phosphatase considerably but had no appreciable effect on serum levels of bilirubin, aminotransferases, or albumin. Furthermore, methotrexate therapy seemed to affect symptoms and histologic progression only minimally. A subgroup of patients with PSC who had cirrhotic stage disease received no apparent beneficial effect from methotrexate therapy. Moreover, the inherent hepatotoxicity, which can lead to hepatic fibrosis, has been known to be associated with long-term methotrexate therapy. Currently, no data support the use of methotrexate for treating PSC; however, the final results of controlled trials are pending.

      Other Immunosuppressive Agents.

      Azathioprine has been used sporadically to treat PSC; two patients seemed to have clinical improvement, and one experienced clinical deterioration.
      • Javett SL
      Azathioprine in primary sclerosing cholangitis [letter].
      • Wagner A
      Azathioprine treatment in primary sclerosing cholangitis.
      Other than these anecdotal reports, no formal studies of aziathioprine therapy for PSC have been performed.

      Ursodeoxycholic Acid.

      Recently, enthusiasm has increased for the use of ursodeoxycholic acid in the treatment of chronic cholestatic liver diseases, including PSC. The rationale for using ursodeoxycholic acid is to replace the bile acid pool with a bile acid that has less toxic potential than, for instance, lithocholic acid. Ursodeoxycholic acid may have an immunologic effect inasmuch as it has been shown to decrease the expression of class I antigens. Although these theories are attractive, clinical evidence supportive of the use of ursodeoxycholic acid therapy for PSC has been mixed (Table 3). An initial controlled clinical trial suggested that a few patients experienced clinical, biochemical, and histologic improvement;
      • Beuers U
      • Spengler U
      • Kruis W
      • Aydemir U
      • Wiebecke B
      • Heldwein W
      • et al.
      Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo-controlled trial.
      however, the results of two recent controlled clinical trials showed that, although ursodeoxycholic acid therapy was associated with biochemical improvement, it had no effect on clinical symptoms of fatigue and pruritus related to PSC nor did it seem to halt histologic progression of the disease.
      • Lo SK
      • Hermann R
      • Chapman RW
      • Fleming KA
      • Shearman J
      • Cusick P
      • et al.
      Ursodeoxycholic acid in primary sclerosing cholangitis: a double-blind placebo controlled trial [abstract].
      • Van Thiel DH
      • Wright HI
      • Gavaler JS
      Ursodeoxycholic acid (UDCA) therapy for primary sclerosing cholangitis (PSC): preliminary report of a randomized controlled trial [abstract].
      Ursodeoxycholic acid was associated with minimal toxicity; however, results of long-term clinical trials must be available before this agent can be recommended in the treatment of PSC.
      Table 3Controlled Clinical Trials That Have Evaluated Ursodeoxycholic Acid Therapy for Primary Sclerosing Cholangitis
      No. of patientsEfficacy
      StudyTreatmentPlaceboDose (mg/kg/day)PruritusBiochemistriesHistology
      Munich
      • Beuers U
      • Spengler U
      • Kruis W
      • Aydemir U
      • Wiebecke B
      • Heldwein W
      • et al.
      Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo-controlled trial.
      6813-15NoYesYes
      Oxford
      • Lo SK
      • Hermann R
      • Chapman RW
      • Fleming KA
      • Shearman J
      • Cusick P
      • et al.
      Ursodeoxycholic acid in primary sclerosing cholangitis: a double-blind placebo controlled trial [abstract].
      81010NoYesNo
      Pittsburgh
      • Van Thiel DH
      • Wright HI
      • Gavaler JS
      Ursodeoxycholic acid (UDCA) therapy for primary sclerosing cholangitis (PSC): preliminary report of a randomized controlled trial [abstract].
      3216<10NoYesNo

      Other Medical Therapies.

      Other agents that have been used to treat PSC in uncontrolled studies include colchicine, cholestyramine, and systemic antibiotics.
      • Lindor KD
      • Wiesner RH
      • Colwell LJ
      • Steiner B
      • Beaver S
      • LaRusso NF
      The combination of prednisone and colchicine in patients with primary sclerosing cholangitis.
      Overall, these agents do not seem to have a beneficial effect on halting the progression of PSC; however, cholestyramine therapy is effective in controlling pruritus, and systemic antibiotics are effective in preventing and treating bouts of bacterial cholangitis.

      Management of Cholestasis.

      Complications associated with chronic cholestatic liver disease include fatigue, pruritus, steatorrhea, fat-soluble vitamin deficiency and its associated consequences, and osteoporosis. Fatigue, although a nonspecific symptom, is a frequent complaint of patients with PSC. Fatigue of notable severity can manifest early during the course of PSC and, generally, parallels progression of the liver disease. Unfortunately, little is known about the specific cause of fatigue; thus, no specific therapy is available for this symptom.
      Pruritus, another common symptom of PSC, can be debilitating and can lead to severe excoriations and a diminished quality of life. Although the pathogenesis of pruritus remains unknown, several hypotheses have been suggested, the most recent of which implies that pruritus may be related to increased availability of endogenous opiate ligands at central opiate receptors.
      • Bergasa NV
      • Jones EA
      The pruritus of cholestasis.
      The theory that endogenous opiates are involved in the pathogenesis of pruritus associated with cholestasis is supported by the following facts: exogenous opiates induce pruritus, cholestasis is associated with increased opiate neurotransmission, and pruritus in the setting of cholestasis can be ameliorated by using opiate antagonists. In general, the severity of pruritus tends not to parallel disease progression in PSC; in fact, during the end stages of PSC, pruritus tends to diminish. Various therapies have been used for pruritus, including cholestyramine, activated charcoal, phenobarbital, rifampin, plasmapheresis, charcoal hemoperfusion, and, recently, opiate antagonists such as naloxone hydrochloride and nalmefene.
      • Bergasa NV
      • Jones EA
      The pruritus of cholestasis.
      • Bachs L
      • Pares A
      • Elena M
      • Piera C
      • Rodes J
      Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis.
      • Gomez RL
      • Griffin Jr, JW
      • Squires JE
      Prolonged relief of intractable pruritus in primary sclerosing cholangitis by plasmapheresis.
      Steatorrhea, associated with fat-soluble vitamin deficiency, has also been described in patients with PSC.
      • Sartin JS
      • Wiesner RH
      • LaRusso NF
      Fat-soluble vitamin deficiencies in primary sclerosing cholangitis [abstract].
      • Munoz SJ
      • Heubi J
      • Deems R
      • Ross R
      • Maddrey WC
      Vitamins D and E deficiency in primary sclerosing cholangitis: mechanism, frequency and relation to deficiency in other lipid soluble vitamins [abstract].
      Fat malabsorption in PSC, as in primary biliary cirrhosis, is most likely related to decreased intestinal concentrations of bile acids.
      • Lanspa SJ
      • Chan AT
      • Bell III, JS
      • Go VL
      • Dickson ER
      • DiMagno EP
      Pathogenesis of steatorrhea in primary biliary cirrhosis.
      In PSC, however, steatorrhea can be caused by chronic pancreatitis or celiac disease, both of which can be associated with PSC.
      • Hay JE
      • Wiesner RH
      • Shorter RG
      • LaRusso NF
      • Baldus WP
      Primary sclerosing cholangitis and celiac disease: a novel association.
      • Borkje B
      • Vetvik K
      • Odegaard S
      • Schrumpf E
      • Larssen TB
      • Kolmannskog F
      Chronic pancreatitis in patients with sclerosing cholangitis and ulcerative colitis.
      • Epstein O
      • Chapman RW
      • Lake-Bakaar G
      • Foo AY
      • Rosalki SB
      • Sherlock S
      The pancreas in primary biliary cirrhosis and primary sclerosing cholangitis.
      Both of these causes of steatorrhea should be considered in the differential diagnosis if steatorrhea occurs in a patient with PSC who has no jaundice or cirrhotic histologic stage disease. Patients who have cirrhosis or jaundice (or both) should be screened for fat-soluble vitamin deficiencies by determining serum levels of vitamins A, D, and E and the prothrombin time. Those patients who have fat-soluble vitamin deficiencies should receive supplemental therapy.
      Metabolic bone disease, osteoporosis in particular, has recently been shown to be a frequent complication in patients with advanced PSC who are undergoing assessment for liver transplantation.
      • Hay JE
      • Lindor KD
      • Wiesner RH
      • Dickson ER
      • Krom RAF
      • LaRusso NF
      The metabolic bone disease of primary sclerosing cholangitis.
      Indeed, bone mineral density levels are often severely decreased in this group; in fact, in 50% of such patients, the levels were below the fracture threshold. Bone mineral densities did not correlate with serum levels of bilirubin, 25-hydroxyvitamin D, fecal fat excretion, or presence or absence of chronic ulcerative colitis. Histomorphometric examination of bone from several of these patients showed increased bone reabsorption, reduced bone formation, and moderate to severe osteopenia with no evidence of osteomalacia. Like primary biliary cirrhosis, the etiopathogenesis of osteopenia remains unknown, and, currently, no effective therapy has been found to prevent or to manage osteopenia associated with chronic cholestatic liver disease.

      Management of Portal Hypertension Associated With Liver Failure.

      The end stages of PSC are frequently associated with complications of portal hypertension, such as esophageal variceal bleeding, ascites, and spontaneous portal-systemic encephalopathy. As with other types of chronic liver disease, esophageal variceal bleeding is best managed with sclerotherapy or variceal banding. Systemic surgical shunting procedures should be avoided, if possible, so the risk of liver transplantation is not increased if it is subsequently indicated. In those patients in whom sclerotherapy for variceal banding fails to stop the variceal bleeding, a transjugular intrahepatic portosystemic shunt (TIPS) should be considered as a bridge to liver transplantation.
      • Conn HO
      Transjugular intrahepatic portal-systemic shunts: the state of the art.
      In patients with PSC who experience other complications of portal hypertension, such as ascites, bacterial peritonitis, and portal-systemic encephalopathy, treatment approaches should be similar to those used for patients with other end-stage liver diseases. A troublesome complication of portal hypertension in the setting of PSC is bleeding from peristomal varices in patients who have undergone proctocolectomy for underlying IBD and who have an ileal stoma (Fig. 6). Bleeding from peristomal varices can be severe, and local measures of ileostomy revision, venous ligation, and injection of sclerosants are usually unsuccessful or provide only temporary relief.
      • Wiesner RH
      • LaRusso NF
      • Dozois RR
      • Beaver SJ
      Peristomal varices after proctocolectomy in patients with primary sclerosing cholangitis.
      Peristomal variceal bleeding can be controlled by performing a surgical portosystemic shunt or a TIPS procedure. Because most of these patients have severe portal hypertension, they are candidates for liver transplantation; thus, performing a TIPS procedure may be a bridge to liver transplantation and, in some patients, may decrease blood transfusion requirements. More important, the complication of variceal bleeding can be prevented by performing an ileoanal anastomosis procedure in patients with PSC who need a proctocolectomy for complications of chronic ulcerative colitis; thus, the formation of an ileal stoma is avoided.
      • Kartheuser AH
      • Dozois RR
      • Wiesner RH
      • LaRusso NF
      • Ilstrup DM
      • Schleck CD
      Complications and risk factors after ileal pouch-anal anastomosis for ulcerative colitis associated with primary sclerosing cholangitis.
      Figure thumbnail gr6
      Fig. 6Peristomal varices surrounding abdominal ileal stoma in patient with primary sclerosing cholangitis who had undergone proctocolectomy and Brooke ileostomy. Patient had daily bleeding from varices before undergoing liver transplantation.

      Management of Complications Specific to PSC.

      Complications that are specific to PSC include the following: (1) bacterial cholangitis, (2) gallbladder and biliary stones, (3) dominant bile duct strictures, and (4) cholangiocarcinoma. Bacterial cholangitis is an unusual initial symptom of PSC but frequently occurs in patients who have had previous biliary surgical treatment or in whom obstructing dominant strictures of the large bile ducts have developed. Back pressure resulting from extensive biliary strictures and the presence of concurrent debris or stones is believed to be partly responsible for the deterioration of liver function and is frequently associated with bacterial cholangitis. Progression of the disease process to cirrhosis and liver failure might be delayed if obstruction is relieved during the early stages of the disease. In treating such situations, endoscopic decompression is an attractive temporary therapeutic alternative because it can be performed with relative ease, can facilitate dilation of multiple strictures at the time the procedure is performed, and eliminates surgical therapy, which might interfere with future attempts of liver transplantation.
      • Gaing AA
      • Geders JM
      • Cohen SA
      • Siegel JH
      Endoscopic management of primary sclerosing cholangitis: review, and report of an open series.
      • Cotton PB
      • Nicki N
      Endoscopic and radiologic approaches to therapy in primary sclerosing cholangitis.
      • Johnson GK
      • Geenen JE
      • Venu RP
      • Schmalz MJ
      • Hogan WJ
      Endoscopic treatment of biliary strictures in sclerosing cholangitis: a larger series and recommendations for treatment.
      The results of open trials suggest that mechanical drainage techniques can alter the usually protracted course of PSC and may delay the timing of and the necessity for liver transplantation. For patients who undergo endoscopic decompression or who have severe intrahepatic disease associated with bacterial cholangitis, long-term, prophylactic broad-spectrum antibiotics are recommended to prevent recurrent bouts of bacterial cholangitis. In such cases, our preference is ciprofloxacin because of its high biliary concentrations and broad spectrum of action against both gram-positive and gram-negative bacteria.
      Cholelithiasis and choledocholithiasis occur in up to 30% of patients with PSC. Chronic cholestasis predisposes to the formation of cholesterol gallstones and bacterial cholangitis; bile stasis predisposes to the formation of pigment stones.
      • Brandt DJ
      • MacCarty RL
      • Charboneau JW
      • LaRusso NF
      • Wiesner RH
      • Ludwig J
      Gallbladder disease in patients with primary sclerosing cholangitis.
      Indeed, diagnosing choledocholithiasis can be extremely difficult in patients with PSC. Therefore, a cholangiogram is essential for eliciting the cause of bacterial cholangitis; if choledocholithiasis is present, stone extraction or surgical intervention may be necessary.
      In approximately 20% of patients with PSC, an obstructing dominant stricture of the biliary tree develops sometime during the course of the disease.
      • Skolkin MD
      • Alspaugh JP
      • Casarella WJ
      • Chuang UP
      • Galambos JT
      Sclerosing cholangitis: palliation with percutaneous cholangioplasty.
      • Bender CE
      • Wiesner RH
      • LeRoy AJ
      • LaRusso NF
      • Nagorney DM
      Long-term benefit of percutaneous dilatation of dominant bile duct strictures in primary sclerosing cholangitis [abstract].
      Frequently, the site of this stricture is the biliary hilum, but strictures can occur in the common bile duct and common hepatic duct. This complication is often associated with the acute onset of jaundice, pruritus, and fever related to bacterial cholangitis. If a dominant stricture is found on cholangiography, cytologic specimens should be obtained in order to exclude bile duct carcinoma, and balloon dilation should be performed with use of either a transhepatic or an endoscopic retrograde approach, depending on the site of the stricture. In general, balloon dilation of dominant strictures and removal of biliary sludge while the patient is receiving antibiotics are effective in alleviating the recent onset of jaundice or pruritus related to this complication. Before balloon dilation or manipulation of the biliary tract is attempted in a patient with PSC, my colleagues and I believe that intravenous administration of antibiotics before and at the time of the procedure is prudent. Approximately 50% of patients with PSC who undergo balloon dilation of dominant strictures will have improvement for up to 2 years.
      • Bender CE
      • Wiesner RH
      • LeRoy AJ
      • LaRusso NF
      • Nagorney DM
      Long-term benefit of percutaneous dilatation of dominant bile duct strictures in primary sclerosing cholangitis [abstract].
      Although some centers have advocated a biliary operation for biliary strictures related to PSC, the absence of prospective controlled data makes it impossible to assess the effect that biliary surgical treatment may have on the natural history of PSC.
      • Cameron JL
      • Pitt HA
      • Zinner MJ
      • Herlong HF
      • Kaufman SL
      • Boitnott JK
      • et al.
      Resection of hepatic duct bifurcation and transhepatic stenting for sclerosing cholangitis.
      Because PSC is generally a progressive disease, biliary surgical intervention should be considered only as a palliative measure aimed at relieving symptoms and excluding cholangiocarcinoma. Investigators agree that biliary surgical treatment has little or no value for patients with PSC who have cirrhosis or for those who have severe intrahepatic bile duct disease. Like surgical shunting procedures, a biliary operation seems to increase the difficulty and risk of liver transplantation and should be avoided if possible.
      Studies show that cholangiocarcinoma may develop in 10 to 15% of patients with PSC.
      • Rosen CB
      • Nagorney DM
      • Wiesner RH
      • Coffey Jr, RJ
      • LaRusso NF
      Cholangiocarcinoma complicating primary sclerosing cholangitis.
      • Miros M
      • Kerlin P
      • Walker N
      • Harper J
      • Lynch S
      • Strong R
      Predicting cholangiocarcinoma in patients with primary sclerosing cholangitis before transplantation.
      The patients at highest risk for such development are those with long-standing chronic ulcerative colitis and cirrhotic stage disease on a liver biopsy specimen. Indeed, my colleagues and I consider PSC a premalignant condition of the biliary tree just as chronic ulcerative colitis is a premalignant condition of the colon. Bile duct carcinomas have been difficult to diagnose early during PSC because no serologic markers exist, and biliary cytologic and histologic analyses have been insensitive for early diagnosis of cholangiocarcinoma. For established biliary carcinoma, biliary cytologic findings are diagnostic in only half the cases. The difficulty in diagnosing cholangiocarcinoma in patients with PSC is supported by a recent report from the University of Pittsburgh in which 10% of patients with PSC who underwent liver transplantation were found to have an unsuspected cholangiocarcinoma.
      • Marsh Jr, JW
      • Iwatsuki S
      • Makowka L
      • Esquivel CO
      • Gordon RD
      • Todo S
      • et al.
      Orthotopic liver transplantation for primary sclerosing cholangitis.
      Patients who have concurrent PSC and cholangiocarcinoma have an overall poor prognosis; less than 10% survive for more than 2 years. Finally, operative management, chemotherapy, and irradiation have not been shown to be useful in these concurrent conditions.
      • Rosen CB
      • Nagorney DM
      • Wiesner RH
      • Coffey Jr, RJ
      • LaRusso NF
      Cholangiocarcinoma complicating primary sclerosing cholangitis.
      In patients with PSC and concomitant cholangiocarcinoma who undergo liver transplantation, bile duct carcinoma has recurred almost universally. Thus, a future challenge is to diagnose cholangiocarcinoma during the early course of PSC. Some recent reports suggest that measuring CA 19–9 levels may be helpful in diagnosing cholangiocarcinoma in patients with PSC.
      • Nichols JC
      • Gores GJ
      • LaRusso NF
      • Wiesner RH
      • Nagorney DM
      • Ritts Jr, RE
      Diagnostic role of serum CA 19–9 for cholangiocarcinoma in patients with primary sclerosing cholangitis.
      Studies to determine whether this test can be used to screen and facilitate early detection of cholangiocarcinoma are currently under way.

      Liver Transplantation.

      The treatment of choice for patients with end-stage PSC is liver transplantation. Recent results show that in patients with PSC who undergo liver transplantation, the 1-year survival rate is 85%, and the 3-year survival rate is 75%
      • Miros M
      • Kerlin P
      • Walker N
      • Harper J
      • Lynch S
      • Strong R
      Predicting cholangiocarcinoma in patients with primary sclerosing cholangitis before transplantation.
      • McEntee G
      • Wiesner RH
      • Rosen C
      • Cooper J
      • Wahlstrom E
      A comparative study of patients undergoing liver transplantation for primary sclerosing cholangitis and primary biliary cirrhosis.
      (Fig. 7). My colleagues and I,
      • McEntee G
      • Wiesner RH
      • Rosen C
      • Cooper J
      • Wahlstrom E
      A comparative study of patients undergoing liver transplantation for primary sclerosing cholangitis and primary biliary cirrhosis.
      however, have found that patients with PSC have an increased incidence of chronic ductopenic rejection that results in graft loss and have an increased incidence of biliary strictures. Moreover, we have found evidence suggestive of recurrent PSC in 5 of 60 patients who have undergone liver transplantation for PSC at our institution. Nonetheless, attributing biliary strictures to recurrent PSC is difficult because bile duct strictures may be due to low-grade bacterial cholangitis, which could be related to the Roux-en-Y bile duct anastomosis that is routinely performed in patients with PSC. In addition, rejection, ischemia, ABO-mismatch, and, possibly, cytomegalovirus or other viral infections are known to contribute to biliary strictures after liver transplantation. These findings were recently confirmed by investigators at the University of Pittsburgh, who evaluated biliary strictures in 643 patients who underwent liver transplantation and a choledochojejunostomy.
      • Sheng R
      • Zajko AB
      • Campbell WL
      • Abu-Elmagd K
      Biliary strictures in hepatic transplants: prevalence and types in patients with primary sclerosing cholangitis vs those with other liver diseases.
      The study revealed that intrahepatic and nonanastomotic extrahepatic biliary strictures occurred significantly more often in patients who underwent liver transplantation for PSC than in those who received allografts for other end-stage liver diseases that necessitated choledochojejunostomy. The investigators concluded that, at least theoretically, the nonanastomotic biliary strictures were possibly caused by recurrent PSC because no other process could be recognized to explain the high prevalence in patients with PSC. Therefore, one must conclude that the incidence and severity of recurrent PSC remain undetermined and that further studies are needed to clarify this important issue.
      Figure thumbnail gr7
      Fig. 7Survival in patients undergoing liver transplantation for primary sclerosing cholangitis (PSC) in comparison with overall survival for all indications of orthotopic liver transplantation (OLTx). Patients undergoing liver transplantation for PSC had significantly improved survival (P<0.01) on the basis of 1992 data from United Network for Organ Sharing (UNOS). Patients with PSC, N = 499; other indications, N = 4,332.
      (From Wiesner RH. Managing complications of PSC and monitoring disease progression. Contemp Intern Med 1994 May; 6:37–46. By permission of Aegean Communications.)
      In addition, patients with PSC who have associated chronic ulcerative colitis remain at increased risk for the development of colon cancer even after they have undergone liver transplantation.
      • Higashi H
      • Yanaga K
      • Marsh JW
      • Tzakis A
      • Katizoe S
      • Starzl TE
      Development of colon cancer after liver transplantation for primary sclerosing cholangitis associated with ulcerative colitis.
      Indeed, at the Mayo Clinic, in more than 90 patients with PSC who had associated chronic ulcerative colitis and had undergone liver transplantation, the occurrence of colon cancer was confirmed in 4. My colleagues and I recommend that patients with PSC who undergo liver transplantation and who have had verified chronic ulcerative colitis for 8 years or more, even if it has been quiescent, should undergo a yearly colonoscopy; biopsy specimens should be screened for evidence of dysplasia.

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