Chapter 18: Biliary complications of liver transplantation 303 5. Biliary complications may present with the following signs and symptoms, except a. abnormal laboratory values b. acute rejection c. abdominal pain d. nausea and vomiting e. fever f. sepsis 6. The advantages of magnetic resonance cholangiography (MRC) in evaluation of suspected biliary complications include a. noninvasive and therapeutic modality b. high sensitivity and specificity for biliary complications c. visualization of the biliary system above and below a biliary stricture d. ideal for identifying biliary leaks e. b and c f. all of the above 7. Complications of percutaneous transhepatic cholangiography (PTC) include a. hemobilia b. cholangitis c. acute rejection d. a and b e. a, b, and c 8. What is the most appropriate diagnostic and therapeutic modality used to evaluate a suspected biliary complication following living donor liver transplantation with CDJ reconstruction? a. endoscopic retrograde cholangiography (ERC) b. PTC c. MRC d. ultrasound e. radionuclide scan 9. All of the following are cited complications of ERC, except a. cholangitis b. pancreatitis c. gastrointestinal bleeding d. acute rejection e. bowel perforation 10. All of the following are possible etiologies of nonanastomotic strictures, except a. hepatic artery thrombosis (HAT) b. chronic rejection c. portal vein thrombosis d. cytomegalovirus infection e. all are associated with nonanastomotic strictures 11. What is the anatomic structure most important in preventing postoperative cholangitis? a. recipient bile duct b. donor bile duct c. sphincter of Oddi d. hepatic veins e. portal vein 12. Cystic duct mucocoeles a. commonly occur but rarely cause complications b. require operative resection and drainage if biliary flow is compromised by the anatomic location of the mucocoele c. usually occur in the early postoperative period d. almost always require conversion to CDJ 13. Clinical questions — a 55-year-old male patient, status post living donor liver transplantation with CDCD reconstruction 2 months prior, presents with fever, chills, malaise, and right upper quadrant abdominal pain. The patient has jaundice, leukocytosis, elevated total bilirubin, and mildly elevated transaminases (aspartate aminotransferase 50 U/L, alanine aminotransferase 65 U/L). 13.1 What is the next appropriate diagnostic tool? a. CT scan b. ERC c. ultrasound d. a or c e. a, b, or c 13.2 Further investigations reveal an anastomotic stricture. What is the most appropriate initial treatment option? a. balloon dilation and biliary stent or drainage tube placement b. immediate operative revision c. supportive care and antibiotics d. a and c e. all 13.3 A balloon dilation is performed and a biliary stent placed across the anastomosis. The patient’s fever and leukocytosis resolve and his total bilirubin returns to normal. What is the appropriate management strategy for the biliary stent? a. remove the stent prior to discharge from the hospital b. repeat ERC at follow-up and if stricture resolves, remove the biliary stent c. leave the stent in place indefinitely References 1. Ca l n e RY, M c M a s t e r P, Po r t m a n n B, e t a l. O b s e r va t i o n s on p r e s- ervation, bile drainage and rejection in 64 human orthotopic liver allografts. Ann Surg 1977;186:282–90. 304 Section 3: Specific conditions 2. Grief F, Bronsther OL, Va Thiel DH. 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Endoscopic manage- ment of biliary fi stulas complicating liver transplantation and other hepatobiliary operations. Ann Surg 1993;218:167–75. 42. Orons PD, Zajko AB. Angiography and interventional proce- dures in liver transplantation. Radiol Clin North Am 1995;33: 541–58. 43. Morelli J, Mulcahy HE, Willner IR, et al. Long-term outcomes for patients with post-liver transplant anastomotic biliary stric- tures treated by endoscopic stent placement. Gastrointest En- dosc 2003;58:374–9. 44. Kok T, Van der Sluis A, Klein JP, et al. Ultrasound and cholangi- ography for the diagnosis of biliary complications after orthotopic liver transplantation: a comparative study. J Clin Ultrasound 1996;24:103–15. 45. Shah AN. Radionuclide imaging in organ transplantation. Radiol Clin North Am 1995;33:473–96. 46. Boraschi P, Braccini G, Gigoni R, et al. Detection of biliary complications after orthotopic liver transplantation with MR cholangiography. Magn Reson Imaging 2001;19:1097–105. 47. 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CHAPTER 19 Primary sclerosing cholangitis Robert Enns 19 OBJECTIVES • By providing an understanding of the pathophysiology of primary sclerosing cholangitis (PSC), the progression of disease and eventual outcomes become logical • To present the various options of therapy — their advantages, limitations, complications, and clinical outcomes • To provide a thorough understanding of the trials that have been performed in PSC, their limitations and where further study is required Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease of unknown etiology, characterized by infl am- mation, destruction, and eventual fibrosis of intrahepatic and extrahepatic bile ducts. Focal strictures of the biliary tree lead to cholestasis and a characteristic beaded appearance on cholangiography [1–4]. The disease may progress silently, or with recurrent episodes of cholangitis characterized by right upper quadrant pain, fever, and jaundice. Insidious, but continuous, progression to cirrhosis with concomitant portal hypertension and liver failure is typical [5–7]. PSC is much less common than alco- holic liver disease; nonetheless, because it often affects oth- erwise healthy young people, it is the fourth most common indication for liver transplantation in the United States [5,8]. Although Delbet first described the syndrome of PSC in 1924, the disease was considered a rare medical curiosity with fewer than 100 cases reported up until 1970 [9,10]. With the advent improved imaging techniques, particularly endo- scopic retrograde cholangiography (ERC) in 1974, the num- bers of cases diagnosed in most major centers increased. Subsequent reviews from the Mayo Clinic and Royal Free Hospital in London spurred further interest in the disease as it was quickly realized that the disorder had an association with infl ammatory bowel disease (IBD), more often affect- ing young males with ulcerative colitis [4,11]. The epidemiology of PSC in regards to the incidence and prevalence of disease in North America was not known until recently. There are no studies involving whole or multiple different states; however, there are at least some regional studies that characterize the epidemiological characteristics of this disorder. A study in Rochester, Minnesota using a medical records linkage system in Olmsted County, Minne- 306 sota has resulted in the soundest, objective data in this re- gard. Between the years 1976 and 2000 the incidence of PSC in men (1.25/100,000 person-years) was twice that of women (0.54/100,000 person-years). The prevalence of PSC, during the same time period, was three times greater in men (20.9/100,000 versus 6.3/100,000) than women. The same study confirmed the findings that 73% of cases have IBD, most of them ulcerative colitis [12]. One of the reasons why the prevalence of this disease ap- pears to be increasing is that the availability of diagnostic tests has increased. Many patients may simply have mildly increased liver enzymes and through thorough investiga- tions be found to have PSC. The widespread implementation of ERCP and MRCP has likely led to a greater number of pa- tients being diagnosed at an earlier stage of the disease, which has also contributed to an improved understanding of the disorder’s classifi cation, pathogenesis, natural history and the clinical, radiographic, and therapeutic modalities deemed appropriate. Classification The early classifi cations of PSC were very rigid and excluded patients with gallstones, previous biliary tract surgery, in- fl ammatory bowel disease, and retroperitoneal fibrosis. Ad- ditionally, progression of disease over a 2-year time period was mandatory prior to the diagnosis [13]. These strict crite- ria seem unjustified and present classifi cation schemes divide sclerosing cholangitis into primary (of unknown etiology) and secondary (with a known or suspected under- lying cause). Present criteria for the diagnosis of PSC are shown in Table 19.1 [7]. Since the majority of patients with PSC have IBD, patients can be further classifi ed as those with Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment, Second Edition Edited By Pierre-Alain Clavien, John Baillie Copyright © 2006 by Blackwell Publishing Ltd Chapter 19: Primary sclerosing cholangitis 307 associated infl ammatory bowel disease and those without [14]. The most common secondary causes of sclerosing cholan- gitis include ischemia (arising from operative trauma, hep- atic arterial infusion of floxuridine, allograft rejection), recurrent biliary sepsis, multifocal cholangiocarcinoma, AIDS, and toxic agents (formaldehyde, absolute alcohol) [15–24]. Radiographically, secondary causes of sclerosing cholangitis simulate PSC but the clinical course and thera- peutic options may differ considerably. There are several other classifi cation schemes that are ac- cepted and used by various interest groups. Caroli and Rosner developed an anatomical classifi cation in which the condi- tion is divided according to whether involvement of the bili- ary tree is diffuse or segmental [25]. Segmental involvement could further be divided into disease that affects the hepatic duct junction, the common hepatic duct, or the common bile duct. Another classifi cation (Table 19.2), devised by Long- mire [26,27], is based on the disease’s clinical course as well as the operative, radiological, and pathological findings in 37 patients at the UCLA Medical Center. Four distinct groups were identified, of which the most common were diffuse PSC associated with IBD (Type 3) or without IBD (Type 4). PSC can also be classified according to other cholangiographic fi ndings (Table 19.3), which have been reported to predict clinical outcomes [28]. Typically, liver biopsy reveals only a paucity of normal bile ducts with nonspecific fibrosis and infl ammation of the por- tal tracts [5,11,29]. The classic onion-skin lesions (Fig. 19.1) are rarely seen on percutaneous biopsy of the liver; therefore, the diagnosis has usually been made through cholangiogra- phy. At least some investigators have suggested that a liver biopsy rarely adds information that changes the clinical management of the patient [30]. Histologically, PSC tends to gradually progress through four reasonably well-character- ized stages [4,31]. Stage 1 is the earliest, characterized by degeneration of epithelial cells in the bile duct and an infl ammatory infiltrate localized to the portal triads. In stage 2, fibrosis and infl ammation infiltrate the hepatic parenchy- ma with subsequent destruction of periportal hepatocytes resu lt i ng i n p ieceme a l nec r o s i s a nd lo s s of b i le duc ts . I n s t age 3, cholestasis becomes more prominent and portal-to-portal fibrotic septa are characteristic. In stage 4, frank cirrhosis develops, with histological features similar to other causes of cirrhosis. In some patients, the findings of large duct obstruc- tion with proliferation and dilatation of interlobular bile ducts may dominate the histological picture. PSC has been noted to be associated with a host of other disorders (Table 19.4). The most common association is with infl ammatory bowel disease, which affects up to 75% of pa- tients with PSC. Of these patients, over 80% have ulcerative colitis (UC) and less than 20% have Crohn’s disease. Con- versely, on ly 2 .5 to 7.5% of pat ients w ith UC have or will de- velop PSC [2–4,29,32–34]. The true prevalence is likely much higher, but because many patients with UC are asymptomatic Table 19.1 Criteria for the diagnosis of primary sclerosing cholangitis. Source: Porayko et al. [7]. 1. Presence of typical cholangiographic abnormalities of PSC (involving bile ducts segmentally or extensively) 2. Compatible clinical, biochemical, and hepatic histologic findings (recognizing that they are nonspecific) 3. Exclude the following in most instances a. Biliary calculi (unless related to stasis) b. Biliary tract surgery (other than simple cholecystectomy) c. Congenital abnormalities of the biliary tract d. AIDS-associated cholangiopathy e. Ischemic strictures f. Bile duct neoplasms (unless PSC previously established) g. Exposure to irritant chemicals (fl oxuridine, formalin) h. Evidence of another type of liver disease, such as primary biliary cirrhosis or chonic active hepatitis Table 19.2 Longmire’s classification of primary sclerosing cholangitis. Source: Longmire [26,27]. Type Frequency Clinical/radiological features (%) 1 5–10 Affecting primarily distal common bile duct 2 5–10 Occurring soon after attack of acute necrotizing cholangitis 3 40–50 Chronic diffuse 4 40–50 Chronic diffuse associated with inflammatory bowel disease Table 19.3 Classification of cholangiographic findings in primary sclerosing cholangitis. Source: Majoie [28]. Type of duct/ Cholangiographic appearance classification Intrahepatic I Multiple strictures, normal caliber of bile ducts II Multiple strictures, saccular dilations, decreased arborization III Only central branches filled, severe pruning Extrahepatic I Slight irregularity of duct contour, no stricture II Segmental stricture III Stricture of almost the entire length of the duct IV Extremely irregular margin, diverticulum outpouchings 308 Section 3: Specific conditions and show only minimal elevation in liver enzymes, cholan- giography is not performed and they may remain undiag- nosed. This may not be an inappropriate practice since early intervention in the disorder has not been demonstrated to improve clinical outcomes. In a recent study from Sweden, the prevalence of UC was 170 /100,00 0 ; of these, 3.7% had PSC . Th is y ield s prevalence for PSC of 6.3 per 100,000 inhabitants [35]. This is similar, al- though not as robust, as the data found in Olmsted County in the United States [12]. A subsequent Swedish study demon- strated that 72% of PSC patients had UC, yielding a total prevalence for PSC of 8 per 100,000 inhabitants [36]. In con- trast to these fi gures are data from Japan, where only 18% of patients with PSC have IBD [37]. Many other disorders, par- ticularly infl ammatory disorders, show an association with PSC.Theseinclude hypereosinophilic syndrome [21,38–40], Sjögren’s syndrome [41], systemic sclerosis [21,42], celiac disease [21,43,44], pancreatitis [45,46], Behçet’s syndrome [47], histiocytosis X, sarcoidosis [48–50], sicca complex [51], rheumatoid arthritis [52], systemic mastocytosis [53], histiocytosis X [54,55], and Reidel’s thyroiditis [56,57]. Figure 19.1 Concentric peribiliary fibrosis and inflammation characteristic of early bile duct damage is typical of primary sclerosing cholangitis. It is not usually seen on liver biopsy specimens because it is has a “patchy” distribution with the highest concentration occurring in the hilum (from where biopsies are not usually obtained). Table 19.4 Disease associations with primary sclerosing cholangitis. Inflammatory bowel disease Pancreatitis Diabetes mellitus Retroperitoneal fibrosis Sarcoid Histiocytosis X Hypereosinophilic syndrome Sjögren’s syndrome Reidel’s thyroiditis Sicca complex Celiac disease Rheumatoid arthritis Chapter 19: Primary sclerosing cholangitis 309 All methods of classifi cation attempt to organize the dis- ease process in the hope of determining which subtypes (particularly predominant common bile duct strictures) may be amenable to radiological, endoscopic, and surgical intervention, in contrast with diffuse disease, which may be amenable only to liver transplantation. Classifi cation, par- ticularly histological, also allows prognostication, which may help identify future transplantation requirements in a timely manner. Etiology Although the etiology of PSC is unknown, several mecha- nisms related to immunological, genetic, toxic, and infec- tious abnormalities have been proposed as contributing factors (Table 19.5). Given the close association of PSC with ulcerative colitis, early investigators postulated that recurrent portal bactere- mia might be an important factor in the development of the disorder. Recurrent portal infection could lead to chronic bil- iary tract infection, infl ammation, and subsequent fibrosis and classical stricture formation [58]. One study even found that portal bacteremia was present in patients who had co- lonic surgery [59]. Subsequent studies, however, could not confirm the findings of portal vein phlebitis [31,58]. Fur- thermore, if recurrent colitis leads to portal vein phlebitis, colectomy (or at least controlled colonic disease) should have a protective effect. This has not been demonstrated to be true [60]. Additionally, hepatic histology does not support portal venous infection since the hallmark of this disorder, portal phlebitis, is mild or absent in most patients with PSC [31]. Thus, there is little evidence to support the colonic-bacterial infection hypothesis. If portal bacteremia from a colonic source is not a critical factor, then toxins that might be released from a diseased colon could be suspect. Theoretically, toxic bile acids such as lithocholic acid, which arise from bacterial activity within the colon, can be absorbed through a diseased colon with its increased mucosal permeability [61]. Lithocholic acid is formed from chenodeoxycholic acid by bacterial 7-α- dehydroxylation in the colon, and it has even been shown to be hepatotoxic in animals. Unfortunately, abnormalities in bile acid metabolism in PSC or UC patients have not been demonstrated. Furthermore, in human tissue, lithocholic acid is rapidly sulfated and rendered nontoxic, a process which does not occur in animal models [62,63]. Other toxic substances that have been considered more re- cently are N-formylated chemotactic peptides, produced by enteric flora, which have been shown in animal studies to in- duce fibrosis and damage to major bile ducts through colonic absorption and enterohepatic circulation. Increased biliary excretion of these peptides has been shown in experimen- tally induced colitis in animal models [64,65]. Further inves- tigation to delineate the role of these peptides in the etiology of PSC is required. The major criticism of the theories of colonic toxins caus- ing PSC comes from studies looking at the natural history of the disorder. It has been demonstrated that the severity of the colitis bears little relation to the development or severity of PSC [32]. Furthermore, patients who have a colectomy show no change in their PSC natural history. Some patients devel- op PSC years after a colectomy or even prior to the onset of their colitis [60]. Some patients who develop PSC never even have infl ammatory bowel disease. Antibiotics (which could, theoretically, alter the colonic flora) appear to have little effect on the natural history of PSC [66]. Because of these findings, colonic toxins are likely to play only a minor role, if any, in the overall etiology of PSC. The association of appendectomy with IBD is an interest- ing one. Appendectomy has been demonstrated to have some interesting associations with UC and UC-associated PSC. In a case–control study in Australia, patients with PSC/UC, PSC alone, and UC were matched to controls in regards to the effects of appendectomy and smoking, and PSC in regards to disease onset, severity, and extent. Appendectomy rates in PSC patients were no different from controls; however, the appendectomy rates in those with UC were four times less than controls, suggesting a protective effect of appendectomy in this patient population. Additionally, those patients with appendectomy in both PSC and UC groups resulted in a 5- year delay in onset of either intestinal or biliary symptoms. The factors responsible for this are not understood; however, infectious or toxic etiologies have again been hypothesized [67]. Abnormalities of copper metabolism have also been impli- cated in the pathogenesis of PSC. Several authors have noted that liver samples from patients with PSC show an excess of hepatic copper, which is known to be hepatotoxic [27,68]. However,unlike other disorders with excessive copper depo- sition, treatment with chelating agents (penicillamine), has not been shown to have any benefit [69]. Likely, as with many cholestatic disorders, copper accumulation is the result of poor biliary excretion, rather than a primary inciting event critical to the pathogenesis of the disorder [70]. Table 19.5 Possible etiologies of primary sclerosing cholangitis. Genetic predisposition Autoimmune Portal infection (bacteremia) Viral infection Colonic toxins Copper toxicity Ischemic injury 310 Section 3: Specific conditions Chronic infection of the biliary tree has been implicated in the pathogenesis of PSC through several observations. Long- mire, who noted that some patients appear to develop PSC after an initial episode of acute necrotizing cholangitis, clas- sified this group as a separate category (type 2) of PSC [26,27]. Patients with acquired immunodeficiency syndrome (AIDS) have been noted to have a s c lero s i ng chola ng i t i s t hat i s felt to be caused by opportunistic infection (i.e. cytomegalovirus, cryptosporidium). Unfortunately,an extensive investigation of 37 PSC patients showed evidence of cytomegalovirus (polymerase chain reaction (PCR) testing of liver tissue) in only one patient [71]. Although reversibility of sclerosing disease in an infectious environment has been demonstrated in immunocompromised patients who have the underly- ing infection treated [72,73], this has not been demonstrated in normal hosts who have a fully functional immune system. Perhaps the infectious organism is difficult to find. Experi- mental cholangitis and biliary atresia can be induced in ani- mal models through infection with Reovirus type 3. Early reports suggested that patients with PSC had a signifi cant in- crease in antibody titers to this virus compared to controls. M o r e r e ce n t d a t a , howe v e r , show n o d i f f e ren c e i n p r eva le n c e or titers of Reovirus between controls and PSC patients [74]. Rubella can also cause an obliterative cholangitis of the in- trahepatic ducts in the fetus, although the histological pic- ture differs from that of PSC [75]. Despite these negative studies, an infectious etiological agent that alters antigenic determinants has yet to be excluded in PSC. Prompted by the observation of familial aggregates of PSC, genetic predisposition has been increasingly reported [76,77]. Several human leukocyte antigens (HLA) mole- cules, including HLA-B8, HLA-DR2, HLA-DR3, and HLA- DRw52 A h ave b e e n fou nd to be ass o c ia ted w it h P SC [ 78 ,79 ] . Interestingly, HLA-B8 and HLA-DR3 are also known to be associated with other autoimmune diseases, which (as noted below) may play an etiological role in PSC. The DRB3*0101 allele, which encodes HLA-DRw52A, has also been most strongly associated with PSC; it is present in 55% of PSC pa- tients compared to 22% of control subjects. Unfortunately, the finding of HLA-DRw52A in 100% of Caucasian North Americans has not been substantiated in European studies [80–84]. Therefore, conflicting data still exist and further re- search is required to identify possible genetic contributions to the etiology of PSC. There is a novel model of PSC in mice using multi-drug- resistance gene (Mdr2) (Abcb4) knockout mice (Mdr2(−/−)) which may have application when it comes to the etiology of disease in PSC [85]. Bile ducts of these mice showed disrupt- ed tight junctions and basement membranes with subsequent bile acid leakage into portal tracts and subsequent induction of a portal infl ammatory infiltrate. Activation of proinfl am- matory and profibrogenic cytokines occurs, leading to the characteristic periductal fibrosis. Sclerosing cholangitis in Mdr2(−/−) mice, therefore, is from a “leaky duct” permeabil- ity issue that results in periductal fibrosis and finally oblitera- tive cholangitis [85]. A second novel, organ-specific model, in rats, in which PSC is induced by intrabiliary administration of 2,4,6- trinitrobenzenesulfonic acid (TNBS) has some signifi cant similarities to human PSC [86]. Unfortunately, when mild stenosis of t he c om mon bi le duc t wa s ach ie ved by s ubtot a l l i- gation and cholangitis induced by TNBS injection no evi- dence of cholangitis, assessed by serum chemistry, histology, or retrograde cholangiography of TNBS-treated rats, oc- curred during long-term follow-up of the rats. Although an- tineutrophil cytoplasmic antibodies were positive in 75% of animals, they were not predictive of liver damage. The au- thors concluded that a single, initial insult is not sufficient to trigger chronic progressive infl ammation and that other fac- tors must be employed to replicate the human disease. Ischemic arteriolar injury, as can occur with patients who receive intra-arterial infusions of floxuridine, can result in diffuse and focal strictures of the intra- and extrahepatic bile ducts similar to PSC, secondary to obliterative thromboen- darteritis [87]. Similar findings can be found in polyarteritis nodosa and in those with hepatic artery thrombosis after liver transplantation [88,89]. Although ischemia can cause a biliary disorder typical of PSC, no specific vascular pathology is found in most patients with PSC [90]. Histiocytosis X has been shown in several patients to be as- sociated with PSC. In three patients reported by Thompson et al., both disorders were demonstrated by pathological evalu- ations to occur in the same patient. The authors suggested that, since the natural history of histiocytosis X is to progress from a proliferative to a fibrous stage, it is a cause of PSC and the two disorders may have a similar pathogenesis. Despite the absence of antimitochondrial, smooth muscle, and nuclear antibodies, accumulating evidence suggests that immune system abnormalities may contribute to the patho- genesis of PSC. The disorder is immune-mediated as opposed to being a classical autoimmune disease. There are a number of immune abnormalities in PSC, including a range of auto- antibodies, portal tract infiltration of T cells, and aberrant expression of HLA molecules on biliary epithelial cells [91]. Initial support for an immune etiology arose from observa- tions that the disorder occurred in concert with other autoimmune diseases, such as ulcerative colitis, Reidel’s thyroiditis, rheumatoid arthritis, and sicca complex. The as- sociation of PSC with HLA-B8 and HLA-DR3, which are typi- cally linked with autoimmune disorders, also supports an autoimmune pathogenesis. Autoantibodies interacting with nuclei of cells infiltrating the portal tract have been charac- terized by Chapman et al. [1,83,92,93]. They have described anticolon and antiportal tract antibodies, of which the latter is more commonly associated with HLA-B8 and, therefore, more specific for patients with PSC. The antigen in obstruct- ed portal ducts was localized to the nuclei of neutrophils and Chapter 19: Primary sclerosing cholangitis 311 since the reactivity of the antibody was primarily perinucle- ar, the antibody was called pANCA. This antibody has been reported in up to 83% of patients with ulcerative colitis and 27% of those with Crohn’s disease. The same pattern has been demonstrated in up to 88% of patients with chronic ul- cerative colitis and PSC [94,95]. The etiological role of pANCA is unclear, but presumably a shared, aberrantly expressed antigenic determinant exists between the biliary tree and the colon that underlies the pathogenesis of the colitis and sclerosis [54]. Further support for an immunological pathogenesis of PSC comes from abnormalities noted in both immune complexes and cellular immunity. Most patients with PSC show in- creased levels of circulating immune complexes, likely re- fl ecting activation of complement through the classic pathway in the serum [96,97]. Abnormalities of cellular immunity have also been observed in patients with PSC. In particular, increased expression of intercellular adhesion molecule-1 (ICAM-1) on biliary epithelium has been noted. ICAM-1 may allow activated T cells to interact with major histocom- patibility complex antigens expressed on biliary epithelium, subsequently leading to infl ammation and fibrosis. In PSC there is an increase in activated T lymphocytes of CD3++HLA DR+ phenotype as compared to healthy subjects (7.9 versus 2.7%, p < 0.01) and also NK cells (12.6 versus 10.3%, respec- tively, p < 0.05) that would support this theory of immune and genetic interplay in the pathogenesis of the disorder [98]. An increased CD4/CD8 ratio within the biliary tree has been noted and this increased proportion of CD8 cells has been found specifi cally in areas of bile duct proliferation, further supporting an immune role for PSC [99–101]. Intercellular adhesion molecule-1 (ICAM-1, CD54) gene polymorphisms have been demonstrated to increase suscep- tibility to IBD and PSC. ICAM-1 is expressed on proliferating bile ducts and interlobular bile ducts and when analyzed in patients for PSC, the E469E homozygote status for ICAM-1 is associated with protection against PSC [102]. Along a similar vein, the recent finding that MadCAM-1 and CCL25 are up- regulated within the liver and not just restricted to the gas- trointestinal tract helps explain why patients may develop PSC many years after a colectomy. In theory, memory lym- phocytes may be present in the liver for many years and re- quire activation by some, as yet unknown, antigen, resulting in up-regulation of the “homing receptors” that activate the infl ammatory cascade [103]. Clinical manifestations PSC predominantly affects males, with a median onset of 40 years of age but a wide range of 1 to 90 years [4]. Pediatric cases show an increased association with immunodeficiency states (10%) and histiocytosis X (15%), and a lesser associa- tion with infl ammatory bowel disease (47%) [104–106]. The male predominance occurs primarily in patients with both PSC and ulcerative colitis. In patients with appendectomy, UC appears to be increased; however, in contrast, appendec- tomy does not seem to be associated with higher PSC rates. PSC is essentially a disease of nonsmokers (decreased risk) whereas ulcerative colitis has an increased risk in smokers [107]. Additionally, the colitis in PSC tends to be milder, for unknown reasons [67]. PSC has been reported in all races [29]. The disorder tends to develop insidiously, with symp- toms present in one study for a mean of 52 months (range 0– 451 months) prior to diagnosis [36]. Symptoms of PSC are often nonspecific initially, but jaundice, right upper quad- rant pain, pruritis, fever, weight loss, and fatigue subse- quently develop (Table 19.6). Atypical presentations of fever of unknown origin or acute supportive cholangitis have been reported. Periodic exacerbations and remissions are typical of the disorder. Exacerbations may be precipitated by gall- stones, which form in a strictured biliary tree where normal flow is impeded [108,109]. Depending on the location of the stones and the strictures, endoscopic or percutaneous treat- ment can be useful in removing a nidus of recurrent infec- tion. Unfortunately, many strictures and stones develop in the proximal biliary tree, which may be less amenable to mechanical intervention. An association with other autoimmune disorders has been noted in patients with PSC. More recently, an association with celiac disease has also been documented [110,111]. With the increased awareness of PSC, availability of ERCP, and use of laboratory screening, more patients who have as- ymptomatic elevations in liver enzymes are being diagnosed with this disorder, particularly if they have underlying ulcer- ative colitis. In particular, asymptomatic elevations of alka- line phosphatase in the setting of chronic ulcerative colitis should raise the suspicion of sclerosing cholangitis and trig- ger further investigation. Early in the course of PSC, the physical examination is normal. As the disease progresses, physical stigmata of chronic liver disease (spider angioma, jaundice, palmar erythema) and hepatosplenomegaly may Table 19.6 Clinical presentation of primary sclerosing cholangitis. Source: Ludwig et al. [31]. Symptom Percent of presentation Jaundice 75–80 Right upper quadrant pain 50–55 Pruritus 30–35 Fever 20–25 Weight loss 15–20 Fatigue 10–15 Asymptomatic 5–10 312 Section 3: Specific conditions become apparent, as well as the development of portal hyper- tension, resulting in ascites and varices. Laboratory evaluations Elevation of cholestatic liver enzymes is typical of this dis- ease. Up to 98% of patients will have an increase in the alka- l i ne phosph ata se level, a lt hough nor ma l a l ka li ne phos phat ase levels have occasionally been recorded, even in symptomatic patients [112]. Most often, the serum alkaline phosphatase is at least twice the upper limit of normal, out of proportion to that of the serum bilirubin. Serum bilirubin levels are also variable (especially early in the course of the disease) but in- evitably, as the disease progresses, elevations occur in con- junction with a gradual decline in serum albumin. Caution must be used in interpreting isolated findings of low albumin as a negative prognostic factor in PSC, as it may also be de- creased by active infl ammatory bowel disease in many pa- tients [5]. Transient worsening of serum transaminases and bilirubin often occurs during exacerbations of the disease. These will often return to near normal when the episode of fever, chills, or right upper quadrant pain has resolved. Serum antinuclear, antismooth muscle, and antimito- chondrial antibodies are negative in over 90% of patients [11,52]. One exception may be an uncommon variant of PSC termed “small duct PSC” (where cholangiography is normal), in which there may be an overlap with autoimmune hepatitis [113,114]. In this disorder, which accounts for only 5% of PSC patients, autoimmune markers may be positive. In patients with clearly defined autoimmune hepatitis, there is also a clear overlap with those with PSC and some of these patients have been characterized. In patients with di- agnosed autoimmune hepatitis, overlap syndrome with PSC should be suspected if patients are male, of young age (<35 years), present with cholestasis, have negative antinuclear antibodies, and have a suboptimal response to immune sup- pression [115]. Hypergammaglobulinemia is found in about 30% of pa- tients and increased IgM levels in 40 to 50% [4,52]. Approxi- mately 65% of patients will have a positive pANCA with HLA-DRw52a (DRB3*0101 allele). pANCA is reported to be higher in patients who have both PSC and UC (68 to 83%) than in patients with PSC and Crohn’s disease (13 to 27%). Similar to Wilson’s disease and primary biliary cirrhosis, hepatic and urinary copper levels are elevated in PSC [68]. The levels appear to correlate with the histological stage of the disorder, thereby providing prognostic information. Serum copper and ceruloplasmin levels are also elevated in 49 and 71% of patients, respectively [27,69,70]. Natural history PSC is a progressive disorder with a variable rate of progres- sion. Progression to cirrhosis has occurred as quickly as 8 months, yet other patients have been symptom free after more than 21 years [81]. The variability in the progression of the disorder has led to the development of staging systems to provide prognostic information to patients and to allow ample time for arrangements for those who are suitable for liver transplantation. Three large, retrospective series have confirmed a median survival (or time to transplantation) of 12 years from the time of diagnosis [2,36,116]. The increased use of laboratory screening of patients with IBD for PSC (with liver enzymes) and increased availability of ERCP likely will lead to detection of the disease at an earlier stage and thus the duration of survival may statistically increase. A subgroup of patients who had no symptoms at the time of diagnosis has also been evaluated. Forty-fi ve patients with no hepatic-related symptoms were followed by the Mayo Clinic for a mean of 6.25 years. Interestingly, 76% demon- strated progression of their liver disease and 31% developed hepatic failure [6]. Other studies have found PSC to be more benign; a Norwegian study showed a mean survival of 17 years after initial diagnosis [117,118]. Although some of the data conflict, it is clear that for most patients, PSC is a progres- sive disorder that within 10 years will signifi cantly affect their health and, eventually, will lead to hepatic failure and death or require liver transplantation. Cox multivariate regression analyses have been performed to determine which factors are important in predicting the prognosis for individual patients with PSC. In a Swedish se- ries of 305 patients, age at diagnosis, histological stage, and serum bilirubin were applied as individual variables to ob- tain a prognostic index [36]. Another regression analysis was performed by the Mayo Clinic: in this analysis, 21 prognostic variables were analyzed individually (in 174 patients with PSC) as predictors in a univariate Cox regression analysis [2]. Of these, five variables were determined to be important pre- dictors of survival: age, bilirubin, hemoglobin, presence or absence of IBD, and hepatic histological stage. In a third retrospective analysis, a multicenter study evaluated 426 patients with PSC and identified four variables — bilirubin, histological stage, age, and splenomeg- aly — as independent variables of prognosis [116,119]. A rela- tively cumbersome mathematical model to predict survival (relative risk) included these variables: R = (0.535 × log bilirubin in mg/dL) + (0.486 × histological stage) + (0.041 × age in years) + 0.705 (if spenomegaly was present) The survival for 1 and 5 years for low-risk patients (R = 2.35 − 2.46) was 0.98 to 0.92. The 1 and 5-year survival for high-risk patients (5.23–5.42) was 0.68 to 0.73 and 0.15 to 0.21 respectively. Modifi cations of this formula have also been devised for liver transplantation and shown to be accurate in studies by Kim et al. [120]. In this abstract, a modified Mayo score was devised using the formula: [...]... presented in Chapter 2 The most common site is the confluence of the left and right main hepatic bile ducts (perihilar: 67% of the cases) [11] The tumor has a tendency to spread along the bile ducts and perineural sheets Distant metastases are rare and are found in only half of autopsies in patients who died from bile duct cancer The tumor typically forms annular structures in the bile ducts and can ulcerate... segment VI of the liver b compression of the right portal vein c enlargement of the perihilar lymph nodes d encasement of the main hepatic artery in the hilar mass 5.3 A PTC is placed and the cholangiography demonstrates occlusion of the bile duct bifurcation with narrowing of the right common bile duct The best surgical option for the patient is a resection of the extrahepatic bile duct and hepaticojejunostomy... Which of the following investigations should be performed next? a ultrasound b PET scan c PTCD d ERCP e cholangio-MRI 5.2 The ultrasound shows dilatation of the intrahepatic bile ducts without dilatation of the extrahepatic bile ducts A CT scan is performed indicating a 2-cm mass in the liver hilum What of the following represents a contraindication for surgery? a presence of a 2-cm mass in segment VI of. .. jaundice early in the course of the disease However, the infiltrative growth pattern and the close proximity to the portal vein and the hepatic artery results in a low resectability rate ranging between 20 and 40% [4,5,27] The tumor is considered nonresectable in the presence of massive involvement of the main portal vein or the hepatic artery, involvement of the hepatic artery or the portal vein in... including the extrahepatic bile ducts c formal right hepatectomy plus segment I and resection of the extrahepatic bile ducts d extended right hepatectomy plus resection of the pancreas head to remove all extrahepatic bile ducts 3 38 Section 3: Specific conditions References 1 Renshaw K Malignant neoplasms of the extrahepatic bile ducts Ann Surg 1922;76:205–21 2 Stewart H, Lieber M, Morgan D Carcinoma of the. .. description by DurandFardel in 184 0 [1] The first systemic review of the literature was performed by Stewart et al in 1940 [2] In 1965, the surgeon Gerald Klatskin reported the first series of patients with cholangiocarcinoma of the hepatic hilum, and introduced the concept of radical resection of the diseased bile duct [3] However, at this time surgery was associated with high morbidity and mortality rates... local bile duct resection versus combined bile duct and liver resection [6,11,21,27] Curative resection, either as local bile duct resection or combined with liver resection, results in a 3- and 5year survival between 40 and 50% and between 20 and 40%, respectively (Table 20.1) [11,12,16– 18, 20–22,25,29,31–45] Resection with tumor positive margins (R1) is associated with a 3- and 5-year survival of 18 and. .. (Chapter 8) Nimura et al [32] reported an acceptable mortality of 8% and a 5-year survival of 41% after combined bile duct and portal vein resection for cholangiocarcinoma However, other authors [ 18, 43] reported less favorable results with a 5-year survival below 5% after extensive vascular resection The indication for extensive surgery including resection and reconstruction of the portal vein and the hepatic... rate of 9% Advances in endoscopic and percutaneous techniques during the last decade offer new and safer access to the biliary tree Stents can be inserted in 90% of the patients with obstructive jaundice Cholangitis is the most frequent complication after stent placement, occurring in 7% of the cases and is associated with a 30-day mortality of 10% [56] The various techniques of biliary drainage are often... but there was no beneficial effect demonstrated on serum hepatic biochemistry Regarding histology, there was progression of disease in 9 out of 10 patients on placebo and but in only 11 out of 20 on therapy The incidence of side-effects was relatively low and included paresthesias and hypertrichosis, but no serious renal toxicity was noted [ 181 , 182 ] 3 18 Section 3: Specific conditions Tacrolimus (FK-506) . delineate the role of these peptides in the etiology of PSC is required. The major criticism of the theories of colonic toxins caus- ing PSC comes from studies looking at the natural history of the. understanding of the pathophysiology of primary sclerosing cholangitis (PSC), the progression of disease and eventual outcomes become logical • To present the various options of therapy — their. cholangiography of TNBS-treated rats, oc- curred during long-term follow-up of the rats. Although an- tineutrophil cytoplasmic antibodies were positive in 75% of animals, they were not predictive of liver