7/27/2019 CHAPTER 68 (1).docx

1/28

CHAPTER 68Sclerosing Cholangitis and Recurrent Pyogenic Cholangitis

Sclerosing cholangitis encompasses a spectrum of cholestatic conditions that arecharacterized by patchy inflammation, fibrosis, and destruction of the intrahepatic and

extrahepatic bile ducts. These conditions are typically chronic, progressive disorders in

which persistent biliary damage may lead to biliary obstruction, biliary cirrhosis, andhepatic failure, with associated complications. The first description of sclerosing

cholangitis is credited to Delbet in 1924.[1]

Although considered for many years to be an

extremely rare disorder, the advent of endoscopic retrograde cholangiopancreatography

(ERCP) in the 1970s has allowed an improved understanding of the true prevalence of thisdisorder and facilitated careful study of its natural history. Nevertheless, many aspects of

sclerosing cholangitis remain poorly understood; most notably lacking are a detailed

knowledge of its etiology and proven effective medical therapy.

A cholangiographic appearance of diffuse stricturing and segmental dilatation of the biliary

system, designated sclerosing cholangitis, may be observed in many distinct conditions.The most frequent isprimary sclerosing cholangitis(PSC), an idiopathic disorder that

usually occurs in association with inflammatory bowel disease (IBD) but may develop

independently. PSC may also be associated with a wide variety of fibrotic, autoimmune,

and infiltrative disorders, although whether such associations imply a commonpathogenesis or epiphenomena is unclear (Table 68-1). PSC is also associated with various

immunodeficiency states; in such cases biliary abnormalities may be caused by infection

with an opportunistic pathogen. The termsecondary sclerosing cholangitisrefers to aclinical and radiologic syndrome that is similar to PSC but develops as a consequence of a

known pathogenesis or injury. Obstructive, toxic, ischemic, and neoplastic causes of

secondary sclerosing cholangitis have been described (see Table 68-1). This chapter

focuses on PSC and recurrent pyogenic cholangitis.

Table 68-1-- Classification and Diseases Associated with Sclerosing Cholangitis

Primary Sclerosing Cholangitis (PSC)

Pri ncipal Disease Associations

Inflammatory bowel disease

Crohn's colitis or ileocolitis

Ulcerative colitis

Other Di sease Associati ons

Systemic disease with fibrosis

Inflammatory pseudotumor

Mediastinal fibrosis

Peyronie's disease

Pseudotumor of the orbit

Retroperitoneal fibrosis

Riedel's thyroiditis

7/27/2019 CHAPTER 68 (1).docx

2/28

Autoimmune or Collagen Vascular Disorders

Autoimmune hemolytic anemia

Celiac disease

Chronic sclerosing sialadenitis

Membranous nephropathyRapidly progressive glomerulonephritis

Rheumatoid arthritis

Sj?gren's syndrome

Systemic lupus erythematosus

Systemic sclerosis

Type I diabetes mellitus

Alloimmune Diseases

Hepatic allograft rejection

Hepatic graft-versus-host disease after bone marrow transplantationInfiltrative Disease

Hypereosinophilic syndrome

Histiocytosis X

Sarcoidosis

Systemic mastocytosis

Immunodeficiency

Congenital immunodeficiency

Combined immunodeficiency

DysgammaglobulinemiaX-lined agammaglobulinemia

Acquired immunodeficiency

Acquired immunodeficiency syndrome

Angioimmunoblastic lymphadenopathy

Selective IgA deficiency

Secondary Sclerosing Cholangitis

Obstructive

Autoimmune pancreatitis

Biliary parasites

Caroli's disease

Choledocholithiasis

Chronic pancreatitis

Congenital abnormalities

7/27/2019 CHAPTER 68 (1).docx

3/28

Cystic fibrosis

Choledochal cyst

Fungal infection

Recurrent pyogenic cholangitis

Surgical stricture

Toxic

Intra-arterial floxuridine (FUDR)

Intraductal formaldehyde or hypertonic saline (echinococcal cyst removal)

Ischemic

Hepatic allograft arterial occlusion

Paroxysmal nocturnal hemoglobinuria

Toxic vasculitis (FUDR)

Vascular trauma

Neoplastic

Cholangiocarcinoma

Hepatocellular carcinoma

Lymphoma

Metastatic cancer

PRIMARY SCLEROSING CHOLANGITIS

DIAGNOSIS

No standardized criteria for the diagnosis of PSC have been universally adopted. Earlydiagnostic criteria included diffuse intra- and extrahepatic bile duct strictures occurring in

the absence of prior biliary surgery or cholelithiasis and after exclusion ofcholangiocarcinoma.

[2]These criteria were later modified because of the recognition that

the clinical spectrum of PSC is broader than initially appreciated, and strict adherence to

the original criteria underestimates the prevalence of the disease. It is now apparent that a

form of PSC, termedsmall-duct PSC, involves only the intrahepatic biliary tree, withoutobvious extrahepatic duct abnormalities.

[3]In addition, both cholelithiasis and

choledocholithiasis may develop as a consequence of PSC, and their presence does not

exclude a diagnosis of underlying PSC.[4,5]

Furthermore, cholangiocarcinoma is a relatively

common complication of PSC, and both conditions frequently coexist.[6]

The diagnosis of PSC is based on typical cholangiographic findings in the setting of

consistent clinical, biochemical, serologic, and histologic findings as well as exclusion ofsecondary causes of sclerosing cholangitis. The characteristic cholangiographic findings are

multifocal stricturing and ectasia of the biliary tree. Areas of narrowing are interspersed

with areas of normal or near-normal caliber and of post-stenotic dilatation. Although themajority of patients with PSC have coexisting abnormalities of the intra- and extrahepatic

bile ducts, a small percentage have an isolated lesion. Patients with small-duct PSC may

7/27/2019 CHAPTER 68 (1).docx

4/28

have a normal cholangiogram. Gallbladder abnormalities, including tumors, may exist in up

to 41% of patients with PSC.[7]

ERCP is considered the standard for establishing a diagnosis of PSC but carries a risk for

complications of up to 10% in patients with PSC.[8,9]

Magnetic resonance

cholangiopancreatography (MRCP) has largely replaced ERCP for diagnosticcholangiography as a result of improvements in image quality and the noninvasive nature

of MRCP (Fig. 68-1). In the few studies that have compared MRCP and ERCP in patients

with PSC, MRCP has demonstrated comparable sensitivity for the detection of biliary

structuring,[10-13]

although performance and interpretation of magnetic resonancecholangiograms vary with the technique and institution. ERCP has the advantage of

combining high-resolution cholangiography with the potential for advanced diagnostic and

therapeutic interventions, including brush cytology or intraductal biopsy for the diagnosis

of cholangiocarcinoma, balloon or catheter dilation of strictures, biliary stent placement,sphincterotomy, and stone removal. Percutaneous transhepatic cholangiography (THC) may

also yield diagnostic images and allow therapeutic intervention but requires percutaneous

puncture and may be technically difficult if the intrahepatic bile ducts are not sufficientlydilated (see Chapter 70).

Patients with IBD and a cholestatic pattern of liver biochemical test elevations shouldundergo imaging of the hepatobiliary system because of the relatively high pretest

probability of PSC. Ultrasonography or computed tomography (CT) may be useful for

planning further diagnostic and therapeutic strategies in selected patients, but they are

usually insufficient for a diagnosis of PSC because normal findings do not exclude thediagnosis. The decision as to which method of cholangiography to perform must be

individualized. In most cases, ERCP is the initial test of choice for patients in whom a

therapeutic intervention or the need for brush cytology is anticipated. In an asymptomaticpatient with mild liver biochemical abnormalities who is unlikely to require therapeutic

intervention, MRCP is the preferred initial test if the images are reliable.[13]

When MRCP is

nondiagnostic and clinical suspicion for PSC remains, diagnostic ERCP is indicated.

Differential Diagnosis

In a patient with a cholangiographic appearance characteristic of sclerosing cholangitis,secondary causes of sclerosing cholangitis must be excluded (see Table 68-1). Patients with

the acquired immunodeficiency syndrome (AIDS) and a CD4+T-lymphocyte count below

100/mm3can exhibit a cholangiographic appearance identical to that of PSC; this entity is

termedAIDS cholangiopathy. Cryptosporidium, Microsporidium, cytomegalovirus, and

other organisms have been isolated from the bile of affected patients.[14,15]

Exposure of thebile ducts to toxins such as intra-arterial floxuridine (FUDR)

[16]and formaldehyde

7/27/2019 CHAPTER 68 (1).docx

5/28

administered to treat a hydatid cyst, when the cyst communicates with the biliary tract,[17]

can produce a similar cholangiographic appearance.

After these secondary causes of sclerosing cholangitis are excluded, distinguishing PSC

from other disorders of the bile ducts may still be challenging. Choledocholithiasis and

cholangiocarcinoma may both develop in conjunction with, or independent of, PSC. In thepresence of extensive choledocholithiasis or diffuse cholangiocarcinoma, identifying

underlying PSC may be difficult. Cholangiographic findings in patients with cirrhosis from

causes other than PSC may at times be mistaken for PSC; however, cholangiography in

cirrhotic patients without PSC typically shows diffuse intrahepatic attenuation of bile ductswithout the ductal irregularity or stricturing seen in patients with PSC.

Primary biliary cirrhosis(PBC) is another chronic cholestatic condition that shares some

clinical features with PSC (see Chapter 89); however, PBC predominantly affects middle-

aged women, has no association with IBD, and is associated strongly with high titers of

antimitochondrial antibodies. Whereas liver histologic findings in the two disorders overlapsubstantially,

[18]the distinction between the two is readily apparent on cholangiography.

Patients with advanced PBC may demonstrate smooth tapering and narrowing of the

intrahepatic bile ducts, but ductal irregularity or strictures are not seen and extrahepatic

lesions do not occur. Antimitochondrial antibody-negative PBC (autoimmune cholangitis)may be difficult to distinguish from small-duct PSC because serologic profiles and

cholangiographic findings may overlap, but the demographic and histologic features of the

two disorders are distinct (see Chapter 89).

Autoimmune hepatitismay also be difficult to distinguish from PSC (see Chapter 88). In the

pediatric population, PSC typically manifests with features of autoimmune hepatitis, andcholangiography is necessary to distinguish the two disorders (see Chapter 62).

[19]With use

of a standardized scoring system for the diagnosis of autoimmune hepatitis, 7.5% of

patients with PSC are characterized as definite or probable for the diagnosis of

autoimmune hepatitis, thereby underscoring the need for cholangiography when PSC issuspected.

[20]Features suggestive of autoimmune hepatitis include female predominance, a

hepatocellular rather than cholestatic pattern of liver biochemical test abnormalities,

hypergammaglobulinemia, high titers of antinuclear and anti-smooth muscle antibodies,histologic evidence of periportal necroinflammation, and clinical response to glucocorticoid

therapy. An overlap syndrome between PSC and autoimmune hepatitis has been described;

it consists of a mixed cholestatic and hepatocellular pattern of liver biochemical testabnormalities, the presence in serum of autoantibodies including antineutrophil cytoplasmic

antibodies (ANCA), cholangiography consistent with PSC, and histologic evidence of

periductular fibrosis as well as periportal necroinflammation.[21,22]

A disorder of the pancreaticobiliary tree termed autoimmune pancreatitis,sclerosing

pancreatocholangitis, or immunoglobulin (Ig) G4associated cholangitishas been

described.[23]

This disorder shares cholangiographic and clinical features with PSC butdiffers in its responsiveness to glucocorticoid therapy. Serum levels of IgG4 are often

elevated in this disorder, and high numbers of IgG4 positive lymphocytes (>20 per high-

powered field) are identified in pinch biopsies obtained from the major papilla or bile ductand may be diagnostic. Although specific diagnostic criteria for this disorder are still

7/27/2019 CHAPTER 68 (1).docx

6/28

emerging, persons without IBD who present with symptoms and cholangiographic findings

consistent with PSC should undergo measurement of serum IgG4 levels as well as

endoscopy and biopsy of the major papilla to exclude IgG4-associated cholangitis (see

Chapter 59).[23-25]

EPIDEMIOLOGY

Determination of the true incidence and prevalence of PSC is complicated by the variable

presentation of the disease, inconsistent diagnostic criteria, and referral bias inherent inmany published studies. Two population-based studies have provided the most accurate

epidemiologic estimates of PSC in Western populations. On the basis of these studies

performed in the United States and Norway, the incidence of PSC is estimated to be 0.9 to1.3 per 100,000, and the point prevalence is estimated to be 8.5 to 13.6 per 100,000.

[26,27]

Although PSC has been diagnosed in neonates and as late as the eighth decade of life, most

patients present between the ages of 25 and 45 years, with a mean age of approximately 39years.

[19,28-33]Approximately 70% of patients with PSC are men,

[27-31]but in the subset of

patients without IBD, the male-to-female ratio is lower (0.72:1).[34]

Women with PSC are

generally older at diagnosis.[27,35]

PSC is also associated with nonsmoking, an effect thatcannot be explained entirely by the association between ulcerative colitis (UC) and

nonsmoking.[36,37]

PRIMARY SCLEROSING CHOLANGITIS AND INFLAMMATORY BOWEL

DISEASE

The relationship between PSC and IBD is striking and incompletely understood.

Approximately 80% of all patients with PSC have concomitant IBD.[27-29,31,38,39]

Conversely, PSC is present in 2.4% to 4.0% of all patients with chronic UC and 1.4% to3.4% of patients with Crohn's disease.[35,38,40,41]Of patients with both PSC and IBD,

approximately 85% to 90% have UC and the remainder have Crohn's colitis or ileocolitis.

The association with IBD is stronger with more extensive colonic involvement; theprevalence of PSC is approximately 5.5% in those with pancolitis, in contrast to 0.5% inthose with only distal colitis.

[35]PSC is not thought to occur in association with Crohn's

disease isolated to the small intestine. Racial differences in the association between PSC

and IBD may exist; concomitant IBD is seen in only 21% of Japanese patients with PSC.[42]

Despite the strong association between PSC and UC, the two diseases often progress

independently of each other.[43]

Although IBD is typically diagnosed before PSC, UC maybe newly diagnosed years after liver transplantation for end-stage liver disease caused by

PSC. Conversely, PSC may be diagnosed years after total proctocolectomy for UC.[44,45]

Whether PSC differs clinically in patients with and without concomitant IBD is unclear.

Older reports demonstrated no histologic[46]

or cholangiographic[47]

differences between

patients with or without IBD. One study,[34]

however, suggested that patients without IBDare more likely to be female, have disease isolated to the extrahepatic ducts, and be

symptomatic at the time of diagnosis. Of the multiple multivariate analyses performed to

identify risk factors for progression of PSC (see later), only one found that the presence of

7/27/2019 CHAPTER 68 (1).docx

7/28

IBD has a significant independent effect on progression of PSC.[29]

Some patients without

overt IBD may have subclinical histologic changes detected in the colon or may develop

overt colitis at a later date.[43]

Therefore, a high index of suspicion for the emergence of

IBD is warranted, and colonoscopy with random biopsies of the colonic mucosa isrecommended for all patients with a new diagnosis of PSC.

ETIOLOGY AND PATHOGENESIS

The etiology and pathogenesis of PSC remain poorly understood. Genetic and immunologicfactors appear to play key roles in disease susceptibility and progression. The importance of

nonimmunogenetic (infectious, vascular, toxic) factors remains controversial. Currently, the

most attractive model of disease pathogenesis postulates that PSC represents animmunologic reaction that develops in immunogenetically susceptible persons who are

exposed to an environmental or toxic trigger, such as bacterial cell wall products. Any

theory of the pathogenesis of PSC must explain the strong association with IBD.

Genetic Factors

The importance of genetic factors in the pathogenesis of PSC is demonstrated by familial

occurrence of the disease and its associations with specific human leukocyte antigen (HLA)

haplotypes. Although uncommon, familial clustering of cases of PSC have been

reported.[48,49]

Furthermore, PSC is strongly associated with specific HLA haplotypes. Earlystudies described an overrepresentation of HLA B8 and DR3 in patients with PSC; these

haplotypes are also associated with other autoimmune disorders such as myasthenia gravis

and autoimmune hepatitis.[50,51]

These findings are not explained simply by the associationbetween PSC and IBD because HLA B8 and DR3 are not overrepresented in patients with

IBD but without PSC. The subsequent development of molecular genotyping demonstrated

that the most common allele in patients with PSC is DRB3*0101, which encodes the

DRw52a antigen. One study found this allele in 100% of 29 patients with PSC whounderwent liver transplantation,

[52]but subsequent studies have demonstrated this allele in

only 50% to 55% of patients with PSC.[53-55]

Currently, the extended HLA haplotypes that

are most strongly associated with PSC are as follows:[53,55,56]

B8-TNF*2-DRB3*0101-DRB1*0301-DQA1*0501-DQB1*0201;

DRB3*0101-DRB1*1301-DQA1*0103-DQB1*0603; and

DRB5*0101-DRB1*1501-DQA1*0102-DQB1*0602.

Haplotypes associated with protection from PSC include the following:

DRB4*0103-DRB1*0401-DQA1*03-DQB1*0302 and

MICA*002.

The strongest association maps to the HLA class I/III boundary on chromosome 6p21.

Strong disease associations have been identified with the MICA*008 allele[57]

and thetumor necrosis factor -2 allele.

[58,59]Despite the multiple HLA associations described,

however, a single HLA-encoded gene that determines susceptibility to PSC appears

unlikely. More likely are multiple HLA susceptibility loci, which may explain in part why

7/27/2019 CHAPTER 68 (1).docx

8/28

PSC is a relatively rare disease even though the HLA haplotypes associated with PSC are

relatively common in populations of Northern European descent.

Also controversial is whether specific haplotypes are associated with disease outcomes.

One study suggested a poor prognosis in patients with PSC and HLA DR4,[60]

but this

finding was not confirmed.

[55]

A more recent multicenter study involving 256 patients withPSC showed that the heterozygous haplotype DR3,DQ2 was associated with a greater risk

of liver transplantation or death and the DQ6 haplotype was associated with a decreased

risk of disease progression.[61]

The relationship between several non-major histocompatibility complex (MHC) genes and

susceptibility to PSC has also been investigated. An initial study reported an associationwith polymorphisms in the gene encoding matrix metalloproteinase 3 (MMP-3) and

postulated a role for MMP-3 in progression of PSC because of its ability to regulate fibrosis

and immune activation.[62]

A subsequent report, however, did not confirm an association

between either MMP-1 or MMP-3 polymorphisms and PSC.[63]

Similarly, no associationsbetween PSC and polymorphisms in the interleukin (IL)-1 or IL-10 genes have been

noted.[64]

Immunologic Factors

Evidence suggests that the immune system plays a key role in the etiology andpathogenesis of PSC, including the multiple associations between PSC and other

autoimmune disorders. The most frequently associated autoimmune disorders include type I

diabetes mellitus and Graves' disease, which are more common in patients with PSC andIBD than in patients with IBD alone.

[65]In addition, as described earlier, an overlap

syndrome that includes features of both PSC and autoimmune hepatitis has been

described.[21,22,66]

In rare cases, well-characterized autoimmune hepatitis may evolve into

sclerosing cholangitis, suggesting that both diseases may be part of the same clinicalspectrum.

[67]Unlike most other autoimmune disorders, however, PSC has an approximately

2:1 male predominance, is not associated with disease-specific autoantibodies, and does not

exhibit a consistent clinical response to immunosuppressive therapy.

A wide range of serum autoantibodies are found in patients with PSC, although none is

specific for the disease. Whether any of these associated antibodies plays a key role in thepathogenesis of the disease process or whether they represent simple epiphenomena is

unclear. Antinuclear antibodies may be present in 24% to 53%, anti-smooth muscle

antibodies in 13% to 20%, and an atypical perinuclear ANCA (pANCA) in 65% to 88% of

patients with PSC.[68-75]

Antibodies directed against cardiolipin, bactericidal/permeability-increasing protein, cathepsin G, and lactoferrin have also been detected.[74-75]Antibodies

directed against an epitope shared by colonic and biliary epithelial cells have been

demonstrated and may suggest a mechanism for the association between IBD and PSC.[76]

Autoantibodies that bind to human biliary epithelial cells (anti-BEC) have been shown to

induce expression of IL-6 and the cell adhesion molecule CD44; this finding could

represent a potential mechanism for the inflammatory bile duct destruction seen in patientswith PSC.

[77]

7/27/2019 CHAPTER 68 (1).docx

9/28

Abnormalities of both humoral and cellular immunity have been described in patients with

PSC. They include an increase in circulating immune complexes, deficient clearance of

immune complexes, and activation of the classical pathway of the complement system.[78-80]

Serum elevations of IL-8 and IL-10 also suggest exaggerated humoral immunity.[81]

Someof the abnormalities in cellular-mediated immunity that have been described include a

decrease in circulating CD8

+

cytotoxic T cells,

[82]

increased numbers of T cells inperipheral blood as well as portal areas of the liver,[83]

and overrepresentation of V3 T-cellreceptor gene segments in hepatic (but not peripheral) T-cell populations.

[84]

Biliary Epithelial Cells

The role of biliary epithelial cells in the pathogenesis of PSC remains unclear. Biliaryepithelial cells could serve as a trigger and a target for immune-mediated injury. Biliary

epithelial cells have been shown to express MHC class II antigens[85]

and adhesion

molecules such as intracellular adhesion molecule-1 (ICAM-1)[86]

and could play a role as

antigen-presenting cells to T lymphocytes. The expression of these molecules can beregulated on biliary epithelial cells by various cytokines, including IL-2 and interferon-.

[87]

Biliary epithelial cells, however, may not express the co-stimulatory ligands necessary for

activation of T lymphocytes.[88]

In addition, many of the same findings are seen in patients

with PBC and extrahepatic bile duct obstruction as well, making it less likely that they playa primary pathogenic role in PSC.

[85]

Infectious and Toxic Factors

The strong association between PSC and colitis has provoked the theory that penetration ofinfectious or toxic agents through an inflamed colon into the portal system may play an

important role in the pathogenesis of PSC. Bile culture results have been positive in

explanted livers in a majority of patients with PSC, although the number of bacterial strains

has correlated inversely with the time since the last endoscopic intervention.[89]In addition,bacterial endotoxin has been shown to accumulate in biliary epithelial cells in patients with

PSC and PBC.[90]

In patients with AIDS cholangiopathy, a variety of organisms, including

Cryptosporidium,Microsporidium, and cytomegalovirus, have been isolated from thebile.

[14,15]A study that evaluated serologic profiles in 41 patients with PSC found a higher

percentage with Chlamydialipopolysaccharide antibodies than in a large control

population. No association was seen with any other microorganisms, including

Mycoplasmaand 22 viruses tested.[91]

Further study is necessary before a direct link

between PSC and Chlamydia, or any other infectious agent, can be established.

A loss of normal colonic mucosal barrier because of inflammation could allow portalinflow of noninfectious toxins. Toxic damage leading to sclerosing cholangitis has been

demonstrated in humans as well as animal models. Biliary exposure to caustic agents[17]

or

hepatic artery infusion of chemotherapeutic agents such as FUDR[16]

can produce acholangiographic appearance identical to that of PSC. In a rat model, administration of the

biliary toxin -naphthylisothiocyanate led to the development of a chronic cholangitis

similar to sclerosing cholangitis in humans.[92]

The toxic injury hypothesis, however, doesnot explain why PSC is not associated with the severity of colonic inflammation in patients

7/27/2019 CHAPTER 68 (1).docx

10/28

with IBD and why PSC may develop years after a patient has undergone total

proctocolectomy.

Vascular Factors

Ischemia has been postulated to play a role in the pathogenesis of PSC because a similarcholangiographic appearance may be found after surgical trauma to the biliary vascular

supply[93]

and after hepatic artery thrombosis or arterial fibrointimal hyperplasia after liver

transplantation.[94,95]

In addition, PSC is associated with the presence of autoantibodies suchas pANCA and anti-cardiolipin antibodies. These autoantibodies, in turn, are strongly

associated with vasculitides such as Wegener's granulomatosis, polyarteritis nodosa, and

thrombotic syndromes. These associations suggest that immune-mediated vascular injuryplays a role in the pathogenesis of PSC.

NATURAL HISTORY AND PROGNOSTIC MODELS

PSC is typically a progressive disease, although the natural history is incompletelyunderstood.[29-31,96-98]

The disease may be considered to progress through the following fourclinical phases, although some phases may not develop or be apparent in an individual

patient:

1. Asymptomatic phase: Patients may have cholangiographic evidence of PSC but normal

serum liver biochemical values and no symptoms. These patients typically are

identified as a result of incidental findings on imaging studies.

2. Biochemical phase: Patients remain asymptomatic but have biochemical abnormalities,

typically elevations of serum alkaline phosphatase levels with variable elevations of

serum bilirubin and aminotransferase levels.

3. Symptomatic phase: Symptoms of cholestasis or liver injury, or both, develop.Pruritus, fatigue, symptoms of cholangitis, and jaundice may occur, often in

combination.

4. Decompensated cirrhosis: The final phase is characterized by worsening symptoms

and complications of end-stage liver disease, such as ascites, encephalopathy, andvariceal bleeding.

This model of disease progression provides a useful framework for understanding the

variability of the natural history in studies of patients with PSC.

Asymptomatic Primary Sclerosing Cholangitis

Asymptomatic patients with PSC make up 15% to 44% of cohorts examined in publishedstudies

[29,31,32,98,99]Some reports have suggested that asymptomatic patients typically have a

benign course of disease. Helzberg and colleagues[98]

reported on 11 asymptomatic patients

with PSC who were followed for a mean of 37 months, and all 11 remained asymptomaticwithout evidence of progressive disease. By contrast, Porayko and colleagues

[99]followed

45 asymptomatic patients with PSC for a median of 6.25 years, and during the surveillance

period, liver failure, resulting in liver transplantation or death, developed in 13 (31%).

7/27/2019 CHAPTER 68 (1).docx

11/28

Overall, symptoms developed in 24 (53%), and progressive liver disease, demonstrated by

new symptoms or signs, worsening cholangiographic findings, or progressive liver

histologic abnormalities, developed in 34 (76%) patients. The Kaplan-Meier estimate of

median survival free of liver failure in this study was 71% at seven years for theasymptomatic patients, significantly lower than the 96% expected on the basis of an age-,

sex-, and race-matched U.S. control population. Differences in the rates of progressionbetween these studies[98,99]

may be the result of differences in patient populations, thedefinition of asymptomatic, and the duration of clinical follow-up.

Symptomatic Primary Sclerosing Cholangitis

Patients with symptoms at the time of diagnosis generally have a worse prognosis thanasymptomatic patients.

[29,30]The clinical stage is likely more advanced at the time of

diagnosis in symptomatic patients, who have more severe biochemical derangements, more

abnormalities on cholangiography, and a higher histologic stage on liver biopsy specimens

than asymptomatic patients. Wiesner and colleagues[29]

compared the natural history ofPSC in 37 asymptomatic patients with that in 137 patients who were symptomatic at the

time of diagnosis. After a mean follow-up of six years, 55 (40%) of the symptomatic

patients had died, compared with 4 (11%) in the asymptomatic group. The Kaplan-Meier

estimate of median survival for the entire cohort was 11.9 years; for the symptomaticcohort, the estimated median survival was between 8 and 9 years. Farrant and colleagues

[30]

described the natural history of PSC in 126 patients, of whom 84% were symptomatic.

After a median follow-up of 5.8 years, the estimated median survival was 12 years. Similarfindings were reported in a large study by Broome and colleagues.

[31]In 305 patients with

PSC followed for a median of 5.25 years, of whom 44% were asymptomatic, the estimated

median survival was 12 years. Patients who were symptomatic at the time of entry into the

study had a significantly worse expected survival (9.3 years) than asymptomatic patients. Astudy of 174 patients with PSC by Ponsioen and colleagues

[97]suggested a better overall

prognosis, with a median expected survival of 18 years. The reason for improved survival

in this most recent study is not known, but patient data were predominantly from the 1990s,compared with data from the 1970s and 1980s in the other studies described. Although

therapeutic advances were not dramatic in the interim, earlier diagnosis in the 1990s may

have led to differences in patient selection that appeared to affect outcomes.

Small-Duct Primary Sclerosing Cholangitis

Patients who have histologic, biochemical, and clinical features of PSC but a normal

cholangiogram are considered to have small-duct PSC, which accounts for 5% to 20% of

all patients with PSC.[3,100]

Three studies have performed extended clinical follow-up inpatients with small-duct PSC.[100-102]In these studies, 12% to 17% of patients progressed to

classic large-duct PSC over long-term follow-up, although the true rate may be higher

because cholangiograms were not obtained routinely in all patients. Cholangiocarcinoma

did not develop in any patient over a median follow-up of 63 to 126 months, and survival inthe small-duct PSC group was better than that of matched control groups with classic

PSC.[100-102]

Therefore, small-duct appears to represent an early stage of PSC, may progress

to large-duct PSC in a small percentage of patients, and is associated with a betterprognosis than classic PSC.

7/27/2019 CHAPTER 68 (1).docx

12/28

Prognostic Models

Natural history studies have provided insight into specific clinical, biochemical, andhistologic features of PSC that may influence prognosis. Whereas early studies described

individual factors that were associated with poor survival in PSC, subsequent studies

utilized multivariable regression analysis techniques, such as Cox proportional hazardsanalysis, to develop more sophisticated mathematical models to predict survival. Such

models predict expected survival for a specific patient at a specific time. This information

is essential for counseling patients about their prognosis and planning future care, such as

liver transplantation.

Multivariable prognostic models that have been developed to predict survival in patientswith PSC are shown in Table 68-2. In an early multivariable analysis, hepatomegaly and a

serum bilirubin level > 1.5 mg/dL were found to be independently associated with a poor

prognosis in PSC. The patient's age, histologic findings, presence of concomitant IBD, and

pattern of cholangiographic involvement did not correlate independently with survival inthis study.

[98]Wiesner and colleagues

[29]developed a prognostic model based on age, serum

bilirubin level, hemoglobin value, presence or absence of IBD, and histologic stage. With

this model, three risk groups (low, intermediate, high) were formed, and predicted survival

curves were shown to be similar to observed survival curves. Farrant and colleagues[30]

developed a multivariable prognostic model in which hepatomegaly, splenomegaly, serum

alkaline phosphatase level, histologic stage, and age at presentation were found to be

important independent factors. Dickson and colleagues[103]

then presented a modeldeveloped from a multicenter collaboration in which data from 426 patients with PSC were

pooled. In this analysis, the patient's age, serum bilirubin level, histologic stage, and

presence of splenomegaly were found to correlate independently with survival, and the

model was validated against the observed survival data in a subgroup of the entire cohort.Broome and colleagues

[31]found the patient's age, histologic stage, and serum bilirubin

level to be independent predictors of survival in 305 patients with PSC, but this prognostic

model was not validated independently. Most recently, Kim and colleagues,[104]

using easilyobtainable clinical and biochemical factors, revised an earlier predictive model that did not

require liver biopsy and did not rely on subjective physical findings such as splenomegaly

or hepatomegaly. This revised natural history model (revised Mayo risk model) found the

patient's age, serum bilirubin level, serum aspartate aminotransferase (AST) level, andserum albumin level and a history of variceal bleeding to be independent predictors of

survival. The model was generated from data on 529 patients from 5 centers and was

validated using data from another center that had not been used in the development of the

model.

Table 68-2-- Independent Predictors of Survival and Prognostic Index Formulas Usedin Natural History Models of Primary Sclerosing Cholangitis*

MAYO CLINIC

MODEL[29]

KING'S

COLLEGE

MODEL[30]

MULTICENTER

MODEL[103]

REVISED MAYO

MODEL[104]

Predictors of Survival

7/27/2019 CHAPTER 68 (1).docx

13/28

MAYO CLINIC

MODEL[29]

KING'S

COLLEGE

MODEL[30]

MULTICENTER

MODEL[103]

REVISED MAYO

MODEL[104]

Age

BilirubinHistologic stage

Hemoglobin

IBD

Age

Hepatomegaly

Histologic stage

Splenomegaly

Alkaline

phosphatase

Age

Bilirubin

Histologic stage

Splenomegaly

Age

Bilirubin

Albumin

AST

Variceal

bleeding

Prognostic Index Formula

R = 0.06 ? age +

0.85 ?loge(min[bilirubin or

10])

4.39 ?loge(min[hemoglobin or

12]) +

0.51 ? histologic stage

+

1.59 ? indicator for IBD

R = 1.81 ?

hepatomegaly +

0.88 ?

splenomegaly +2.66 ? log(alk

phos) +

0.58 ? histologicstage +

0.04 ? age

R = 0.535 ?

loge(bilirubin) +

0.486 ? histologicstage +

0.041 ? age +

0.705 ?

splenomegaly

R = 0.03 ? age +

0.54 ?

loge(bilirubin) +

0.54 ? loge(AST)+

1.24 ? variceal

bleeding

0.84 ? albumin

Alk phos, alkaline phosphatase; AST, aspartate aminotransferase; IBD, inflammatory

bowel disease; min, minimum of; R, risk score.

*Superscript numbers indicate references.Age expressed in years, bilirubin in mg/dL; hemoglobin in gm/dL; alkaline phosphatase

in U/L; AST in U/L; albumin in g/dL.

Values for IBD, hepatomegaly, splenomegaly, and variceal bleeding are 1 if present, 0 ifabsent.

The Child (Child-Pugh) classification may also be used to predict survival in patients with

PSC (see Chapter 90). Shetty and colleagues[105]

found that Kaplan-Meier seven-year

survival rates for patients with Child class A, B, and C cirrhosis caused by PSC were89.8%, 68%, and 24.9%, respectively. Subsequent evaluation, however, suggested that the

Child classification is less accurate than the revised Mayo risk model, especially forpatients with early-stage PSC.

[106]

Despite the cumbersome nature of the mathematical formulas used in the various natural

history models, these models can be useful in the clinical care of patients with PSC. Theymay facilitate selection for and timing of liver transplantation by comparing predicted

survival with readily available post-liver transplantation survival rates. The availability of

multiple models with differing prognostic variables, however, may be confusing in clinical

7/27/2019 CHAPTER 68 (1).docx

14/28

practice. The models also may not account for other clinical events, such as the

development of cholangiocarcinoma or variceal bleeding, that may affect prognosis in

patients with PSC. Further refinement of these prognostic models, including consensus on

the use of specific prognostic variables, may ultimately clarify their role in clinical practice.

CLINICAL FEATURESSymptoms

The initial clinical presentation of PSC can be quite varied and may run the gamut fromasymptomatic elevations of serum alkaline phosphatase levels to decompensated cirrhosis

with jaundice, ascites, hepatic encephalopathy, or variceal bleeding. The most common

symptoms at the time of presentation include jaundice, fatigue, pruritus, and abdominalpain.

[19,28-33,107,108]Other associated symptoms may include fever, chills, night sweats, and

weight loss (Table 68-3). The onset of these symptoms is typically insidious, although an

acute hepatitis-like presentation has been described.[40]

Increasingly, PSC is diagnosed in an

asymptomatic or minimally symptomatic stage. Large series have shown that 15% to 44%of patients with PSC are asymptomatic at the time of diagnosis,

[29,31,32,98,99]probably

because of the routine liver biochemical screening in patients with IBD, as well as the

widespread availability of MRCP and ERCP for evaluating elevated serum alkaline

phosphatase levels.

Table 68-3-- Most Common Symptoms and Signs at the Time of Diagnosis of PrimarySclerosing Cholangitis

Symptoms Rate (%)

Fatigue 65-75

Abdominal pain 24-72

Pruritus 15-69

Fever/night sweats 13-45

Asymptomatic 15-44

Weight loss 10-34

Signs

Jaundice 30-73

Hepatomegaly 34-62

Splenomegaly 32-34

Hyperpigmentation 14-25

Ascites 4-7

Data from references 19, 29-33, 98, 99, 107, 108.

Symptoms of PSC are often intermittent. Episodes of pruritus, jaundice, abdominal pain,

and fever are typically interspersed with asymptomatic periods of varying duration.[39,107,108]

7/27/2019 CHAPTER 68 (1).docx

15/28

The intermittency of the symptoms is thought to reflect intermittent biliary obstruction

caused by microlithiasis and sludge.[5,109]

This obstruction may predispose to cholestasis

and induce an acute inflammatory reaction. Secondary bacterial infection may result in

low-grade cholangitis and predispose to pigment stone formation.[5]

Physical Examination

Physical findings may be normal in patients with PSC, particularly those who are

asymptomatic. When physical abnormalities are present, the most common includehepatomegaly, jaundice, and splenomegaly (see Table 68-3). Skin findings are common and

include cutaneous hyperpigmentation, excoriations resulting from pruritus, and xanthomata.

As liver disease progresses, spider angiomas, muscular atrophy, peripheral edema, ascites,and other signs of advanced liver disease may appear.

[28-30]

Laboratory Findings

Chronic elevation of serum alkaline phosphatase levels, typically three to five timesnormal, is the biochemical hallmark of PSC. A normal alkaline phosphatase level, however,may be found in up to 6% of patients with cholangiographically proved PSC.

[110,111]In

some cases, an advanced histologic stage has been demonstrated on a liver biopsy specimen

despite normal serum alkaline phosphatase levels.[110]

Serum aminotransferase levels are

typically elevated, although rarely above four to five times normal except in the pediatricpopulation.

[112]The serum bilirubin level may be normal or elevated and often fluctuates.

When the serum bilirubin level is elevated, the bilirubin is predominantly conjugated.

Reductions in the serum albumin level and prolongation of the prothrombin time mayreflect hepatic synthetic dysfunction with advanced liver disease. In addition, malnutrition

and underlying IBD may lower serum albumin levels. Vitamin K malabsorption related to

cholestasis may play a role in prolonging the prothrombin time. Other nonspecific

consequences of cholestasis are elevations in serum copper, serum ceruloplasmin, andhepatic copper levels, increased urinary copper excretion, and elevated serum cholesterol

levels.

Several immunologic markers and serum autoantibodies are found in the majority of

patients with PSC, although none is specific for the disease. Hyperglobulinemia is frequent;

serum IgM levels are elevated in up to 50% of patients, and IgG and IgA levels also may beelevated.

[28,29,28,107]Antinuclear antibodies, often in low titer, may be detected in 24% to

53% of patients. Anti-smooth muscle antibodies are found in 13% to 20% of patients, but

antimitochondrial antibodies are found in less than 10%.[26,28,70,73,75]

Most commonly found

in patients with PSC are pANCA,[72]

which are detected in 65% to 88% of patients andappear to react to a heterogeneous group of antigens.[70,71,74,75]These antigens have been

found to represent neutrophil nuclear envelope proteins predominantly, and the

corresponding antibodies have been referred to as antineutrophil nuclear antibodies(ANNA).

[113]In contrast to Wegener's granulomatosis, titers of pANCA do not appear to

correlate with disease activity, severity, or response to medical therapy in patients with

PSC.[72]

Furthermore, the presence of autoantibodies does not appear to differ in patientswith and without IBD. Anti-cardiolipin antibodies are detected in 66% of patients with

PSC, and the titer has been reported to correlate with disease severity.[75]

In general, despite

7/27/2019 CHAPTER 68 (1).docx

16/28

the high frequency of autoantibodies in patients with PSC, a clear association between the

presence of these antibodies, pathogenesis of the disease, and prognosis or response to

treatment remains unproved. Measurement of autoantibodies is therefore of limited clinical

value in patients with PSC.

Imaging Findings

Cholangiography by ERCP, MRCP, or percutaneous THC establishes a diagnosis of PSC

and provides information regarding the distribution and extent of disease. The characteristiccholangiographic findings include multifocal stricturing and ectasia of the biliary tree.

Areas of narrowing are interspersed with areas of normal or near-normal caliber and areas

of post-stenotic dilatation. The result is a classic beaded appearance to the biliary tree.The strictured segments are usually short, annular, or band-like in appearance (Fig. 68-2),

although longer confluent strictures may be seen in more advanced disease. Localized

segments of dilated ducts may have a saccular or diverticular appearance. Major areas of

focal, tight narrowing known as dominant stricturesmay be seen and often involve thebifurcation of the hepatic duct.

[114]At times, diffuse involvement of the intrahepatic biliary

tree may give a pruned appearance that is difficult to distinguish from the diffuse

intrahepatic duct attenuation seen in patients with cirrhosis of any cause; irregularity of the

duct wall or concomitant involvement of the extrahepatic bile duct supports a diagnosis ofPSC.

Figure 68-2.Endoscopic retrograde cholangiopancreatography (ERCP) in two patients

with primary sclerosing cholangitis (PSC).A,ERCP with contrast injected through a

balloon catheter (seen in distal bile duct). The intrahepatic ducts are mainly affected and

show diminished arborization (pruning), with diffuse segmental strictures alternating withnormal-caliber or mildly dilated duct segments (cholangiectasias), resulting in a beaded

appearance.B,ERCP in a patient with PSC. Radiologic features include diffuse

irregularity of the intrahepatic ducts, multiple short strictures and cholangiectasias, small

diverticula in the wall of the common hepatic duct (arrow), and clips from a priorcholecystectomy.

Both the extrahepatic and intrahepatic bile ducts are abnormal in approximately 75% ofcases. The intrahepatic ducts alone may be involved in 15% to 20% of cases.

[28,31,35,107]

Abnormalities of the extrahepatic biliary tree in the absence of intrahepatic involvement are

less common.[98,99]

The cystic duct and gallbladder may be involved in up to 15% of

patients but may not be well visualized on routine cholangiography.[115]

Pancreatic ductirregularities similar to those seen in chronic pancreatitis may rarely be noted.[116]

PATHOLOGY

Gross and histologic specimens from the extrahepatic bile ducts demonstrate a diffusely

thickened, fibrotic duct wall. The fibrosis is accompanied by a mixed inflammatoryinfiltrate that may involve the epithelium and biliary glands.

[117,118]Florid hyperplasia of the

biliary glands with accompanying neural proliferation has been described.[119]

Examination

7/27/2019 CHAPTER 68 (1).docx

17/28

of PSC explants removed at the time of liver transplantation has demonstrated areas of thin-

walled saccular dilatation, termed cholangiectasias, that correspond to the beaded

appearance on cholangiography.[120]

A wide range of liver biopsy findings may be seen in patients with PSC. For this reason,

histologic findings are not typically diagnostic for PSC. The characteristic bile duct lesionis a fibro-obliterative process that may lead to an onionskin appearance of concentricfibrosis surrounding medium-sized bile ducts (Fig. 68-3); however, this finding is seen in

less than one half of biopsy specimens.[117,121,122]

The smaller interlobular and septal bile

duct branches may be entirely obliterated by this process, resulting infibro-obliterativecholangitis. This finding is present in only 5% to 10% of biopsy specimens but is thought

to be virtually pathognomonic of PSC.[121]

In this process, the biliary epithelium may

degenerate and atrophy and be replaced entirely by fibrous cords. Other characteristic

histopathologic findings may include bile duct proliferation, periductal inflammation, andductopenia. The degree of inflammation can be quite variable but is typically a portal-based

mixture of lymphocytes, plasma cells, and neutrophils with a periductal focus. Lymphoid

follicles or aggregates may also be seen.[121,122]

The histologic progression of PSC can be divided into four stages, analogous to a similar

staging system in PBC[46]

(See Chapter 89). In stage I (portal stage) changes are confinedto the portal tracts and consist of portal inflammation, connective tissue expansion, and

cholangitis. Stage II (periportal stage) is characterized by expansion of inflammatory and

fibrotic processes beyond the confines of the limiting plate, resulting in piecemealnecrosis (interface hepatitis) and periportal fibrosis. Depending on the degree of biliary

obstruction, ductular proliferation and cholangitis may be of varying severity. Stage III

(septal stage) is characterized by fibrous septa that bridge from one portal tract to the next.

Bridging necrosis may occasionally be seen but is uncommon. Stage IV (cirrhotic stage)implies progression to biliary cirrhosis. The degree of inflammatory activity may subside asthe stage of disease progresses, and focal bile ductular proliferation may be striking. A

study that examined the time course of progression through the histologic stages revealedthat for patients with stage II disease, 42%, 66%, and 93% progressed to a higher histologic

stage at one, two, and five years, respectively.[123]

For patients initially with stage II

disease, progression to biliary cirrhosis (stage IV) occurred in 14%, 25%, and 52%,

respectively. Regression of stage was observed in 15% of patients and probably reflectedsampling variability in the histologic assessment.

Many of the histologic findings of PSC are nonspecific and may be seen in other disorders.

In particular, the histologic distinction between PSC and PBC may be difficult to discern.

In one study, histologic examination could classify only 28% of patients who had one of

the two diseases.[18]When lymphocytic interface hepatitis is prominent, the distinction fromautoimmune hepatitis may be challenging, especially because hypergammaglobulinemia

and autoantibodies may be present in both conditions. In addition, an overlap syndrome

with features of both PSC and autoimmune hepatitis has been described.[21,22,66]

Whensevere cholestasis develops, hepatic copper accumulation can be dramatic and may mimic

that seen in Wilson disease.[124]

COMPLICATIONS

7/27/2019 CHAPTER 68 (1).docx

18/28

Cholestasis

The complications associated with all causes of chronic cholestasis may develop in patientswith PSC (see also Chapters 20 and 89). Pruritus is one of the most common symptoms of

PSC and may adversely affect a patient's quality of life. Severe excoriations and

debilitating symptoms may develop. The pathogenesis of pruritus in chronic cholestasis ispoorly understood, and response to therapy is inconsistent (see Chapter 89). The

accumulation of bile acids in the plasma and tissue of cholestatic patients has been cited as

a potential cause of pruritus, and the pruritus of cholestasis is typically treated with oral

administration of bile-acid binding resins such as cholestyramine. Not all patients withelevated serum bile acid levels itch, however. In addition, pruritus is frequently

intermittent, despite the relative stability of serum bile acid levels. Several lines of evidence

suggest that cholestasis is associated with an increased level of endogenous opioids. In

animal models, cholestasis is associated with an increase in plasma levels of endogenousopioids.

[125]In humans, cholestatic patients may experience opiate withdrawal-like

symptoms after the administration of an opioid antagonist. In addition, administration of

naloxone and naltrexone, which have opioid antagonist properties, has been reported torelieve pruritus in cholestatic patients in small clinical trials.[126,127]

Nutritional deficiencies may complicate chronic cholestasis in patients with PSC. Intestinalabsorption of the fat-soluble vitamins A, D, E, and K is particularly affected and is thought

to be related to decreased intestinal concentrations of conjugated bile acids.[128]

Concomitant disease such as IBD, chronic pancreatitis, and celiac disease may alsocontribute to intestinal malabsorption. Clinical consequences include night blindness

(vitamin A deficiency) and coagulopathy (vitamin K deficiency).

The importance of metabolic bone disease, also referred to as hepatic osteodystrophy, is

often underrecognized in patients with PSC. Two forms of metabolic bone disease may

develop: osteomalacia and osteoporosis. With improvements in nutritional management,

osteomalacia (decreased bone mineralization) is now relatively rare, and most bone diseasein cholestatic patients is osteoporosis. Bone mineral density is significantly lower in

patients with PSC than in age- and sex-matched controls.[129]

The pathogenesis of bone

density loss in PSC and other chronic cholestatic liver diseases is unknown. Intestinalmalabsorption of vitamin D is probably not the primary abnormality because serum vitamin

D levels are often normal and vitamin D repletion does not usually have a major impact on

the severity of osteoporosis. In patients with concomitant IBD, the use of glucocorticoidsmay play a role in exacerbating bone loss in patients with PSC. Overall, severe

osteoporosis is less common in patients with PSC than in those with PBC because a

majority of patients with PSC are young men who have a higher baseline bone mineral

density and a slower rate of bone loss than middle-aged women, who account for mostcases of PBC.

Biliary Stones

Cholelithiasis and choledocholithiasis are more common in patients with PSC than in thegeneral population. Gallstones are found in approximately 25% of patients with PSC and

are often pigmented calcium bilirubinate stones.[5]

Biliary strictures may predispose to bile

7/27/2019 CHAPTER 68 (1).docx

19/28

stasis and intraductal sludge and stone formation. Ultrasonography has only an intermediate

sensitivity for detecting intraductal stones. Therefore, patients with PSC and worsening

cholestasis or jaundice should undergo ERCP to distinguish biliary stone disease from the

development of a dominant stricture or cholangiocarcinoma.

Cholangiocarcinoma

Cholangiocarcinoma is a feared complication of PSC and can arise from bile duct

epithelium anywhere in the biliary tract (see Chapter 69). PSC should be considered apremalignant condition of the biliary tree, analogous to the relationship between UC and

carcinoma of the colon. The reported frequency of cholangiocarcinoma in patients with

PSC has ranged from 6% to 11% in natural history studies and from 7% to 36% in patientswith PSC who undergo liver transplantation.

[130,131]Tumors are most commonly found in

the common hepatic duct and perihilar region but may involve only the bile duct,

intrahepatic ducts, cystic duct, or gallbladder. Cholangiocarcinoma remains the leading

cause of death in patients with PSC.

The pathogenesis of cholangiocarcinoma in PSC is poorly understood. Although

cholangiocarcinoma may complicate any stage of the disease, chronic inflammation isthought to predispose to epithelial dysplasia and an increased risk of malignant

transformation. The role of chronic inflammation is supported by the observation that

patients with chronic Clonorchis sinensisand other liver fluke infections are also atincreased risk of cholangiocarcinoma (see Chapter 82).

[132]A role for proinflammatory

cytokines in stimulating oxidative DNA damage and inactivation of DNA repair processes

has been postulated.

Biliary malignancy should be suspected when a patient with PSC exhibits rapid clinical

deterioration with worsening jaundice, weight loss, and abdominal pain. Advanced PSC

without cholangiocarcinoma may present with the identical clinical presentation. Thediagnosis of cholangiocarcinoma presents a particular challenge in patients with PSC. A

malignant biliary stricture may be indistinguishable cholangiographically from the

underlying PSC (Fig. 68-4). Because of the tendency of cholangiocarcinoma to grow insheets as opposed to a discrete mass, cross-sectional imaging with CT or magnetic

resonance imaging (MRI) may be insensitive for detection of cholangiocarcinoma.

Several serum tumor markers of cholangiocarcinoma have been evaluated. Serum CA 19-9

has been the most commonly utilized tumor marker, with one small study reporting a

sensitivity of 89% and specificity of 86% for a serum CA 19-9 level greater than 100 U/mL

in diagnosing cholangiocarcinoma.[133]

A later study from the same group found a lowersensitivity for serum CA 19-9 but a correlation between the CA 19-9 level and tumor stage;

no tumor was resectable in patients with a CA 19-9 level greater than 1000 U/mL.[134]

Another study described a biochemical index using CA 19-9 and carcinoembryonic antigen(CEA) levels (CA 19-9 + (CEA ? 40) > 400), with a reported sensitivity of 86% for

cholangiocarcinoma.[135]

More recent studies, however, suggested a poor sensitivity (33%)

for this combined biochemical index despite a relatively high specificity (85%).[136,137]

7/27/2019 CHAPTER 68 (1).docx

20/28

Obtaining an adequate tissue sample presents a particular challenge in the diagnosis of

cholangiocarcinoma. Dominant strictures resulting from PSC may be indistinguishable

cholangiographically from those harboring cholangiocarcinoma. Brush cytology can be

obtained at the time of ERCP, but the sensitivity of this approach is only 50% to 60% atbest.

[138,139]False-positive results are also possible because chronically inflamed cells may

take on a malignant cytologic appearance. The addition of a sampling technique to brushcytology, such as endobiliary biopsy or fine-needle aspiration (FNA), improvessensitivity,

[138-140]and when clinical or cholangiographic suspicion for cholangiocarcinoma

is high, two tissue sampling techniques should be used. The sensitivity of cytologic

examination is increased by use of specialized techniques such as fluorescent in situhybridization and digital image analysis.

Endoscopic ultrasound (EUS) with FNA has an emerging role in the evaluation of

suspected cholangiocarcinoma when brush cytology and other methods have failed to yielda diagnosis.

[141,142]The sensitivity of EUS-FNA for diagnosing cholangiocarcinoma in

patients with PSC has been reported to be as high as 89%.[141,142]

High-frequency

intraductal ultrasound (IDUS) is under study as a means of discriminating benign frommalignant dominant bile duct strictures, and several studies[143-145]have demonstrated that

the addition of IDUS to ERCP improves the ability to distinguish benign from malignant

dominant bile duct strictures in patients with PSC. Direct endoscopic visualization of bileduct strictures is also possible with the availability of choledoscopy (cholangioscopy) in

clinical practice. A single small study has shown that the addition of choledoscopy to

ERCP in patients with PSC and a dominant stricture enhanced detection of malignancy,

with an overall sensitivity of 92%.[146]

Therefore, in patients with PSC, suspectedcholangiocarcinoma, and negative brush cytology or endobiliary biopsy results, repeat

ERCP plus EUS-FNA, IDUS, or choledoscopy improves the sensitivity of diagnosing

cholangiocarcinoma.

The development of cholangiocarcinoma is an ominous sign, with a median survival of five

months after diagnosis.[6]

In addition, recurrence of cholangiocarcinoma after livertransplantation is nearly universal, and cholangiocarcinoma is generally considered a

contraindication to liver transplantation. Early identification of patients with PSC who are

at high risk of cholangiocarcinoma is crucial so that liver transplantation may be

undertaken before the bile duct cancer develops. One study reported a strong associationbetween current or former smoking and the development of cholangiocarcinoma in patients

with PSC.[147]

A second study, however, could not confirm an association with

smoking.[130]

In addition, duration of PSC, distribution of biliary strictures, and past

medical or surgical intervention do not appear to be associated with an increased risk ofcholangiocarcinoma. Longer duration of IBD has been shown to be a risk factor for

cholangiocarcinoma in some,[148]but not all,[130]studies. Overall, therefore, studies to date

have not defined clear risk factors for cholangiocarcinoma that are clinically useful foridentifying patients with PSC at particularly high risk. Nor has the optimal surveillance

strategy been delineated.

Colonic Neoplasia

7/27/2019 CHAPTER 68 (1).docx

21/28

Most patients with PSC also have IBD; the majority have ulcerative pancolitis. UC isknown to be associated with an increased risk of colonic dysplasia and carcinoma (see

Chapter 112); the risk of colon cancer increases with the duration, extent, and severity of

colitis. For patients with pancolitis, the cumulative risk of colon cancer is approximately5% to 10% after 20 years and 12% to 20% after 30 years.

[149-151]A growing body of

evidence suggests that patients with concomitant PSC and UC are at significantly higherrisk for developing colonic neoplasia (dysplasia or carcinoma) than patients with UCalone.

[152-157]In one report, 132 patients with UC and PSC were compared with a randomly

selected historical cohort of patients with UC but without PSC.[155]

Colonic carcinoma or

dysplasia developed in significantly more patients with both UC and PSC than those withUC alone (25% versus 6%), and significantly more deaths from colorectal cancer were

observed in the patients with PSC (4.5% versus 0%). A similarly designed study included

20 patients with both UC and PSC and 25 matched controls with UC alone.[153]

Colonic

dysplasia was observed significantly more often in patients with both UC and PSC (45%

versus 16%), although the time to the development of dysplasia was similar in the twogroups. Patients with PSC and UC were also more likely than patients with UC alone to

have synchronous sites of dysplasia in the colon. Another study examined 40 patients with

PSC and UC matched with 80 control subjects with UC alone.[152]The cumulative risk ofcolorectal dysplasia or carcinoma in patients with both UC and PSC was 9%, 31%, and

50% after 10, 20, and 25 years, respectively. These rates were significantly higher than

those for the control group (2%, 5%, and 10%, respectively).

The mechanisms by which PSC confers an added risk of colonic neoplasia are not well

understood. A high colonic concentration of secondary bile acids may play a role becausepatients with UC and colonic dysplasia or carcinoma have higher fecal bile acid

concentrations than patients with UC who do not have dysplasia or carcinoma.[158]

This

theory is supported by the higher incidence of right-sided colon cancer in patients with UCand PSC than in those with UC alone.

[155,156]In the study by Shetty and colleagues,

[155]76%

of the colon cancers in patients with UC and PSC occurred proximal to the splenic flexure,

compared with only 20% in patients with UC alone.[155]

Increased colonic secondary bile

acid concentrations may also explain the apparent chemoprotective effect ofursodeoxycholic acid (UDCA) against the development of colonic neoplasia. Two studies

have reported that UDCA use is associated with a lower risk of colonic dysplasia or cancer

in patients with UC and PSC.[159,160]

UDCA may confer protection against colonicneoplasia by reducing colonic concentrations of secondary bile acids, as well as by

affecting expression of protein kinase C isoforms, metabolism of arachidonic acid, and

expression of cyclooxygenase-2.[159-162]

These data need to be confirmed in larger-scale,

prospective trials before UDCA use can be recommended routinely for preventing coloncancer in patients with PSC. Whether UDCA has a chemoprotective effect in patients with

UC but without PSC is unknown.

Patients with PSC who have UC should undergo annual colonoscopic surveillance for the

detection of colonic dysplasia or cancer. As for colonoscopic surveillance in patients with

UC alone, multiple mucosal biopsy specimens should be obtained (see Chapter 112).[163]

Most experts agree that colonoscopic surveillance should start immediately after the

diagnosis of PSC. Surveillance should continue even after liver transplantation because

these patients remain at increased risk for colonic neoplasia.[164-166]

7/27/2019 CHAPTER 68 (1).docx

22/28

Peristomal Varices

Varices at the stoma may develop in patients with PSC and portal hypertension who havepreviously undergone proctocolectomy with ileostomy for IBD.

[167,168]These varices may

bleed spontaneously, and the bleeding may be dramatic. Treatment modalities that may

initially be effective in achieving hemostasis include injection sclerotherapy,

[169]

percutaneous transhepatic coil embolization,[170]

surgical stomal revision,[171]

and

transjugular intrahepatic portosystemic shunt placement (see Chapter 90).[172]

Nevertheless,

recurrent bleeding is common, and liver transplantation should be considered to relieve

portal hypertension and treat the underlying liver disease.

TREATMENT

Except for liver transplantation, no specific therapy has proved effective for treating PSC.The objectives of management should be to treat the complications of disease, such as

flares of bacterial cholangitis, jaundice, and pruritus, and prevent complications, such asosteoporosis and nutritional deficiencies. Other complications such as cholangiocarcinoma

and liver failure should be diagnosed as early as possible to allow the possibility of

treatment.

Medical Treatment of Underlying Disease

A wide variety of medications have been studied in patients with PSC (Table 68-4). Many

of the published studies have been small and uncontrolled with limited follow-up. Becauseof the varied course of PSC, with spontaneous remissions and unpredictable flares,

adequate clinical trials in patients with PSC require long-term follow-up. In addition, the

defined study endpoints, whether clinical, biochemical, histologic, or a mathematical risk

score, have varied greatly among published studies. To date, no medical treatment has beenshown clearly to alter the course of PSC.

Table 68-4-- Medical Therapy for Primary Sclerosing Cholangitis*

NO PROVEN BENEFIT POSSIBLE BENEFIT

Antibiotics

Cholestyramine

Ursodeoxycholic acid (20-30 mg/kg/day)[173-177,180]

Glucocorticoids,

Azathioprine

MethotrexateCyclosporine

Tacrolimus

Pentoxifylline

Colchicine

d-penicillamine

7/27/2019 CHAPTER 68 (1).docx

23/28

NO PROVEN BENEFIT POSSIBLE BENEFIT

Nicotine,

Perfenidone*Superscript numbers indicate references.

UDCA has been the most extensively studied drug in patients with PSC. At least fivecontrolled clinical trials have been reported, with varying doses of UDCA.

[173-177]The

mechanisms by which UDCA is thought to exert a beneficial effect in cholestatic

conditions include protection of cholangiocytes against cytotoxic hydrophobic bile acids,stimulation of hepatobiliary secretion, protection of hepatocytes against bile-acid inducedapoptosis, and induction of antioxidants (see also Chapter 89).

[178,179]In a randomized,

controlled trial by Beuers and colleagues,[173]

patients with PSC treated with UDCA, 13 to

15 mg/kg/day for one year, had significant improvements in biochemical and histologic

endpoints in comparison with those given placebo, but no effect on symptoms was noted.

In the largest controlled trial of UDCA for PSC to date, Lindor and colleagues[176]

randomized 105 patients to UDCA, 13 to 15 mg/kg/day, or placebo for a median of 2.2

years. Significant biochemical improvements were seen with UDCA therapy, but nodifference was seen in the primary endpoint, which was a composite of death, liver

transplantation, histologic progression of at least two stages, hepatic decompensation, or

quadrupling of the serum bilirubin level.

Because of the disappointing results with standard-dose UDCA, several groups have

published results on the use of high-dose UDCA in the treatment of PSC. Mitchell andcolleagues

[177]performed a two-year controlled trial of high-dose UDCA, 20 mg/kg/day,

versus placebo in 26 patients with PSC. Compared with placebo, treatment with high-dose

UDCA led to improvement in biochemical markers and a reduction in the progression offibrosis and cholangiographic changes. In addition, high-dose UDCA was well tolerated,

with no significant adverse events. Harnois and colleagues[180]

performed an open-label

pilot study of UDCA, 25 to 30 mg/kg/day, for one year in 30 patients with PSC and

compared changes in the revised Mayo risk score with those in patients from a previousrandomized trial of standard-dose UDCA. After one year of treatment, improvement in the

revised Mayo risk score in the high-dose UDCA group was significantly greater than that

seen in placebo-treated patients from the prior study but no better than that in the patientstreated with standard-dose UDCA.

With the encouraging results of these two small studies, a larger study was undertaken in

which 219 patients with PSC were randomized to high-dose UDCA or placebo. After fiveyears, no differences in symptoms, liver biochemical abnormalities, quality of life, or

transplant-free survival were found between the two groups.[181]

A subsequent study in 31

patients randomized to low-dose, standard-dose, and high-dose UDCA found improvementin the revised Mayo risk score in all groups, with statistical significance only in the group

receiving high-dose UDCA.[182]

Therefore, the precise benefit of UDCA in general, and

high-dose UDCA in particular, remains uncertain.

7/27/2019 CHAPTER 68 (1).docx

24/28

Given the immunologic alterations in patients with PSC, immunosuppressive therapy

would appear to be a reasonable consideration. Glucocorticoids, administered both orally

and via nasobiliary lavage, have not shown a clear benefit in uncontrolled studies,[183,184]

although subgroups of patients may have a clinical response.[185]

Lack of long-term datademonstrating clear response and concerns about long-term adverse effects, including

exacerbation of metabolic bone disease, have limited the use of glucocorticoids. Oralbudesonide, a newer glucocorticoid with limited systemic toxicity, has been evaluated in anuncontrolled pilot study in 21 patients with PSC.

[186]After one year of therapy, treated

subjects had minimal biochemical or histologic improvement and no change in revised

Mayo risk score. In addition, significant loss of bone mass was seen with use ofbudesonide.

Other immunomodulators also have been evaluated. In a small prospective, controlled trial

of methotrexate, no biochemical, histologic, or cholangiographic differences from therapywith placebo were seen after two years of treatment.

[187]In a small pilot study of tacrolimus

therapy, significant biochemical improvement was observed after one year, but no change

in cholangiographic or histologic severity was documented.[188]

Pentoxifylline, whichinhibits tumor necrosis factor-(TNF-), led to no biochemical or symptomatic

improvements in a one-year pilot study in 20 patients with PSC.[189]

Etanercept, a

recombinant inhibitor of TNF-, also showed no benefit in a small number of patients withPSC.

[190]

Colchicine has been evaluated as a potential therapy for PSC because of its antifibrogenicpotential. In a randomized, controlled clinical trial comparing colchicine therapy with

placebo for three years, no differences were seen between the two groups in rates of

mortality or liver transplantation or in symptoms or biochemical and histologic

findings.[191]

D-penicillamine has also been studied in a randomized, controlled clinicaltrial

[192]because of the increased hepatic copper concentrations seen in patients with PSC

and other chronic cholestatic conditions. In addition to its cupruretic effects, penicillamine

may have antifibrogenic and immunosuppressive properties. Therapy with penicillaminetherapy for three years, however, led to no difference in mortality or in biochemical or

histologic progression as compared with therapy with placebo. In addition, penicillamine

was associated with substantial toxicity. Other studies have failed to demonstrate a

significant response to nicotine[193,194]

or the antifibrotic drug pirfenidone.[195]

Finally,combinations of various agents such as azathioprine, glucocorticoids, UDCA, and

antibiotics have been studied in a limited fashion.[196-198]

The results of these studies have

been mixed, with some showing no benefit and others demonstrating histologic

improvement in small numbers of patients. A problem with combining agents is anincreased risk of adverse drug reactions.

Medical Treatment of Complications

An important component in the medical care of patients with PSC is the management ofcomplications of the disease, such as pruritus, nutritional deficiencies, and bacterial

cholangitis. As discussed earlier, therapy with UDCA does not have a consistent effect on

pruritus, although some patients may notice symptomatic improvement. Although treatmentwith antihistamines may improve pruritus, anion-exchange resins such as cholestyramine,

7/27/2019 CHAPTER 68 (1).docx

25/28

colestipol hydrochloride, or colesevelam are typically more effective, although compliance

is a problem with the use of bile acid resins. These drugs are relatively unpalatable,

frequently produce constipation, and may interfere with the absorption of other

medications. Rifampin appears to be an effective and safe alternative for patients who donot respond to the preceding measures.

[199,200]Opiate antagonists such as naloxone and

naltrexone have also been shown to be effective for cholestatic pruritus, although self-limited episodes of opioid withdrawal-like symptoms may occur.[126,127,201]

Patients who areunresponsive to these measures and who do not obtain relief from endoscopic therapy of a

dominant stricture (see later) may need to be considered for plasmapheresis (which has

shown benefit in anecdotal reports) or even liver transplantation (see also Chapter 89).

Patients with PSC should be screened for nutritional deficiencies by measurement of fat-

soluble vitamin levels and the prothrombin time. In most patients, vitamin supplements are

given orally, but a parenteral route may be necessary in patients with severe intestinal fatmalabsorption. Administration of vitamin A is usually effective for correcting subclinical

vitamin A deficiency. Correction of vitamin D deficiency, with or without calcium

supplements, is of unproven benefit in cholestatic liver disease but is generallyrecommended because of its safety.[202]The use of bisphosphonates and other agents to

promote bone formation requires further study in patients with PSC and osteoporosis. In

patients with PSC, prolongation of the prothrombin time is more likely to be the result ofadvanced liver disease than of vitamin K deficiency, although a trial of oral vitamin K is

warranted in patients with coagulopathy (see Chapters 89 and 92).

Bacterial cholangitis may develop spontaneously or after manipulation of the biliary tree. In

some patients, recurring bouts of bacterial cholangitis can be debilitating. Antibiotic

prophylaxis is indicated in any patient with known or suspected PSC who undergoes

manipulation of the biliary tree via ERCP, percutaneous THC, or surgery. Typically, a five-to seven-day course of a broad-spectrum antibiotic such as a fluoroquinolone,cephalosporin, or beta-lactamase inhibitor is prescribed following biliary manipulation. For

patients with recurring cholangitis, long-term antibiotic prophylaxis may be helpful. Thestandard approach involves rotating antibiotics (e.g., amoxicillin-clavulanate, ciprofloxacin,

and trimethoprim-sulfamethoxazole), given in three- to four-week cycles, in an attempt to

reduce the risk of resistance. In patients with severe, recurrent bacterial cholangitis that

does not respond to this approach, liver transplantation may be the only beneficial option.

Endoscopic Management

Endoscopic therapy for PSC carries the potential to relieve jaundice, pruritus, and

abdominal pain; improve biochemical cholestasis; decrease the frequency of episodes ofbacterial cholangitis; and improve biliary flow. In theory, improved long-term biliary

patency could slow the progression of the disease and prevent or delay biliary cirrhosis.

Studies of endoscopic intervention in patients with PSC, however, have typically been

small, retrospective series and uncontrolled trials, and firm conclusions are not available.

Patients most likely to benefit from endoscopic intervention are those with one or moredominant stricture. These patients are more likely to present with specific symptoms such

as worsening jaundice or pruritus, cholangitis, or abdominal pain. Multiple studies have

7/27/2019 CHAPTER 68 (1).docx

26/28

reported significant improvements in clinical, biochemical, and cholangiographic endpoints

in patients with a dominant stricture treated with endoscopic therapy,[203-207]

usually dilation

with a balloon or graduated dilators, with or without temporary placement of a biliary stent.

Sphincterotomy is often performed for improved access and to treat choledocholithiasis, ifpresent. One retrospective study suggested that balloon dilation followed by stent

placement offered no improvement and increased the risk of complications compared withballoon dilation alone.[208]

Because the study was not randomized, however, these findingsmay have been attributable to differences between the treatment groups.

Three studies have suggested that progression of the underlying disease process may beslowed by endoscopic therapy of a dominant stricture. Baluyut and colleagues

[209]

performed graduated and balloon dilation, with or without stent placement, in 63 patients

with PSC with a median follow-up of 34 months, and demonstrated an observed 5-year

survival that was significantly better than survival predicted from the revised Mayo modelscore (see Table 68-3). Stiehl and colleagues

[210]performed endoscopic balloon dilation and

occasional stent placement in 52 patients with PSC in whom a dominant stricture developed

while the patients were on therapy with UDCA. Actuarial survival free of livertransplantation at three, five, and seven years was significantly better than that predicted

from the multicenter model score (see Table 68-3). Finally, a retrospective chart review by

Gluck and colleagues[8]

reported a single-center 20-year experience with endoscopictherapy for PSC. Endoscopic therapy for a dominant stricture was performed in 84 of 106

patients who underwent a total of 317 procedures during the 20-year observation period.

The patients in whom endoscopic therapy was performed had a significantly higher survival

rate than that predicted by the revised Mayo model score at years three and four. Thesestudies were not randomized trials, and in some cases were retrospective, but they provide

some supporting evidence to suggest that endoscopic management of a dominant stricture

may alter the course of PSC.

Endoscopic therapy in PSC also has important limitations. Complications of ERCP, such as

pancreatitis, cholangitis, worsening cholestasis, and perforation, occur at an overall rate of7.3% to 10%.

[8,210,211]Patients with diffuse intrahepatic biliary stricturing and no dominant

stricture are less likely to derive benefit from endoscopic intervention and may be at higher

risk for post-ERCP cholangitis.[208]

If ERCP is performed in expert hands and only for

specific indications such as worsening of jaundice, pruritus, or cholangitisthat is, in thesubgroup of patients who are most likely to benefit from therapythe risks in patients

unlikely to benefit will be minimized (see Chapter 70).

Percutaneous Management

Percutaneous THC with balloon dilation, stenting, or both, can also be undertaken to treat

biliary strictures in patients with PSC. This approach is typically recommended only when

endoscopic intervention is contraindicated or unsuccessful because of the added risks of

bleeding and bile peritonitis, as well as increased patient discomfort, associated withpercutaneous intervention (see Chapter 70).

Surgical Management

Biliary Surgery

7/27/2019 CHAPTER 68 (1).docx

27/28

The role of biliary surgery in PSC has diminished considerably with improvements inendoscopic therapy and liver transplantation. Resections of a dominant stricture of the bile

duct or near the hepatic bifurcation followed by hepaticojejunostomy or

choledochojejunostomy have been the most commonly performed operations.[212,213]

Postoperative mortality is increased significantly in patients with PSC and cirrhosis.

[214]In

addition, biliary surgery may complicate future liver transplantation. Currently, biliarysurgery in patients with PSC is rarely indicated and should be reserved for the small subsetof patients who have early-stage PSC and biliary strictures that are not amenable to

endoscopic or percutaneous intervention.

Liver Transplantation

Liver transplantation (see also Chapter 95) is the only therapy that has been shown

conclusively to improve the natural history of PSC. In addition, quality of life improves

after liver transplantation.[215,216]

The procedure is recommended for patients with PSC in

whom decompensated cirrhosis and complications of portal hypertension develop.Recurrent cholangitis or pruritus that is refractory to medical and endoscopic management

rarely may also be indications for liver transplantation. Determination of the appropriate

timing for liver transplantation in patients with PSC may be challenging, although use of

available natural history models can be helpful. When a patient's expected survival afterliver transplantation exceeds survival predicted from the natural history models, liver

transplantation should be undertaken, in the absence of contraindications. Intraoperatively,

patients who undergo liver transplantation for PSC should have a Roux-en-Ycholedochojejunostomy anastomosis, instead of a standard choledochocholedochostomy.

This approach is recommended to allow removal of as much of the native biliary tree as

possible, to reduce the risk of recurrent strictures and cholangiocarcinoma.[217]

Patient and graft survival after liver transplantation for PSC is excellent. A large single-

center experience demonstrated 1-, 5-, and 10-year actuarial patient survival rates of 93.7%,

86.4%, and 69.8%, respectively. Corresponding graft survival rates were 83.4%, 79.0%,and 60.5%.

[218]Similar results have been reported in other series.

[219,220]Overall, survival

rates after liver transplantation for PSC are significantly better than those for any other

disease except PBC.[221]

Recipient factors that have been associated with a worse prognosisafter liver transplantation for PSC are older age, decreased serum albumin level, renal

failure, Child's class C cirrhosis, and advanced United Network for Organ Sharing

status.[221,222]

The presence of cholangiocarcinoma has a major impact on the outcome after liver

transplantation for PSC. Early studies demonstrated that even in cases in whichcholangiocarcinoma was discovered incidentally in the explant, recipient survival was poor,

with a one-year survival rate of 30% in one series.[223]

On the basis of such studies,

cholangiocarcinoma has generally been considered a contraindication to liver

transplantation. Another report confirmed the poor post-liver transplantation outcome inpatients with known cholangiocarcinoma but suggested a good survival rate for those who

had a small cholangiocarcinoma found incidentally at the time of transplantation.[220]

Subsequent studies have demonstrated improved results of liver transplantation in patientswith cholangiocarcinoma, with one- and five-year survival rates of 65% to 82% and 35% to

7/27/2019 CHAPTER 68 (1).docx

28/28

42%, respectively.[224,225]

Preoperative chemoradiation in highly selected patients with

cholangiocarcinoma has shown promise in reducing the rate of tumor recurrence after liver

transplantation (see Chapter 69).[226,227]

Biliary strictures commonly recur after liver transplantation for PSC and may represent

recurrent PSC. In addition to recurrent PSC, potential causes of biliary strictures after livertransplantation include ABO blood group incompatibility, hepatic artery occlusion, chronic

ductopenic graft rejection, Roux-en-Yrelated chol