Thursday, May 22, 2008

Primary sclerosing cholangitis (PSC); epidemiology, classification and etiology.


Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease of unknown etiology, characterized by inflammation, destruction, and eventual fibrosis of intrahepatic and extrahepatic bile ducts which can lead to end-stage liver disease.

  • Focal strictures of the biliary tree lead to cholestasis and a characteristic beaded appearance on cholangiography.
  • 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.
  • PSC is much less common than alcoholic liver disease; nonetheless, because it often affects otherwise healthy young people, it is the fourth most common indication for liver transplantation in the US
  • 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
  • With the advent improved imaging techniques, particularly endoscopic retrograde cholangiography (ERC) in 1974, the numbers of cases diagnosed in most major centers increased.
  • Mayo Clinic and Royal Free Hospital in London increased interest in the disease as it was quickly realized that the disorder had an association with inflammatory bowel disease (IBD), more often affecting young males with ulcerative colitis.
  • In one study it was found that 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.
  • One of the reasons why the prevalence of this disease appears to be increasing is that the availability of diagnostic tests has increased.
  • Many patients may simply have mildly increased liver enzymes and through thorough investigations be found to have PSC.
  • The widespread implementation of ERCP and MRCP has likely led to a greater number of patients being diagnosed at an earlier stage of the disease, which has also contributed to an improved understanding of the disorder.

PSC and inflammatory bowel disease

  • UC has been reported in 25 to 90 percent of patients with PSC.
  • A survey of 23 hospitals in Spain, for example, examined the reported cases of PSC from 1984 to 1988; UC was present in 44 percent.
  • It is likely that this figure is an underestimate, since the colonic mucosa may be grossly normal in appearance despite the presence of histologic colitis.
  • The true prevalence of UC in PSC is probably closer to 90 percent when rectal and sigmoid biopsies are routinely obtained.
There are varying reports of the prevalence of PSC in UC.
  • A survey of 1500 patients with UC in Sweden, for example, found that 72 (5 percent) had an elevated serum alkaline phosphatase; endoscopic retrograde cholangiopancreatography (ERCP) was performed in 65, of whom 55 (85 percent) had evidence of PSC.
  • PSC was more prevalent in patients with pancolitis than in those with distal colitis (5.5 versus 0.5 percent).
  • It was also more common in men than women.
  • Another report found that more than 7 percent of patients with UC may have PSC.

PSC also occurs in patients with Crohn's disease.

  • In one report of 262 patients with Crohn's disease, 38 (15 percent) had long-standing abnormal liver biochemical tests and underwent endoscopic cholangiography and liver biopsy.
  • Nine of these patients (3.4 percent) were diagnosed with PSC.


  • Approximately 70 percent of patients with PSC are men, with a mean age at diagnosis of 40 years, even though the sex distribution is equal between men and women in the overall UC population.
  • However, in the small subset of patients without UC, the male:female ratio is lower (0.8:1) and patients are diagnosed at an older age.
  • Women with PSC are generally diagnosed at an older age.


The early classifications of PSC were very rigid and excluded patients with gallstones, previous biliary tract surgery, inflammatory bowel disease, and retroperitoneal fibrosis.
  • Additionally, progression of disease over a 2-year time period was mandatory prior to the diagnosis.
  • These strict criteria seem unjustified and present classification schemes divide sclerosing cholangitis into
    • primary (of unknown etiology) and
    • secondary (with a known or suspected underlying cause).

Criteria for the diagnosis of primary sclerosing cholangitis.
Source: Porayko et al.

  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.
    • Biliary calculi (unless related to stasis)
    • Biliary tract surgery (other than simple cholecystectomy)
    • Congenital abnormalities of the biliary tract
    • AIDS-associated cholangiopathy
    • Ischemic strictures
    • Bile duct neoplasms (unless PSC previously established)
    • Exposure to irritant chemicals (fl oxuridine, formalin)
    • Evidence of another type of liver disease, such as primary biliary cirrhosis or chonic active hepatitis.
Since the majority of patients with PSC have IBD, patients can be further classified as those with associated inflammatory bowel disease and those without

The most common secondary causes of sclerosing cholangitis include
  • ischemia (arising from operative trauma, hepatic arterial infusion of floxuridine, allograft rejection),
  • recurrent biliary sepsis,
  • multifocal cholangiocarcinoma,
  • AIDS, and
  • toxic agents (formaldehyde, absolute alcohol).

Radiographically, secondary causes of sclerosing cholangitis simulate PSC but the clinical course and therapeutic options may differ considerably.

Caroli and Rosner developed an anatomical classification in which the condition is divided according to whether involvement of the biliary tree is diffuse or segmental.

  • Segmental involvement could further be divided into disease that affects the hepatic duct junction, the common hepatic duct, or the common bile duct.

Longmire’s classification of primary sclerosing cholangitis.
Source: Longmire.

Type Frequency Clinical/radiological features (%)

Type -1 5–10% Affecting primarily distal common bile duct

Type -2 5–10% Occurring soon after attack of acute necrotizing cholangitis

Type -3 40–50% Chronic diffuse

Type -4 40–50% Chronic diffuse associated with inflammatory bowel disease

Type of duct/ Cholangiographic appearance classification
Type I Multiple strictures, normal caliber of bile ducts
Type II Multiple strictures, saccular dilations, decreased arborization
Type III Only central branches filled, severe pruning

Type I Slight irregularity of duct contour, no stricture
Type II Segmental stricture
Type III Stricture of almost the entire length of the duct
Type IV Extremely irregular margin, diverticulum outpouchings.

The classic onion-skin lesions are rarely seen on percutaneous biopsy of the liver; therefore, the diagnosis has usually been made through cholangiography.

Histologically, PSC tends to gradually progress through four reasonably well-characterized stages.

Stage 1 is the earliest, characterized by degeneration of epithelial cells in the bile duct and an inflammatory infiltrate localized to the portal triads.
In stage 2, fibrosis and inflammation infiltrate the hepatic parenchyma with subsequent destruction of periportal hepatocytes resulting in piecemeal necrosis and loss of bile ducts.
In stage 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.

Associated disorders

The most common association is with inflammatory bowel disease, which affects up to 75% of patients with PSC.

  • Of these patients, over 80% have ulcerative colitis (UC) and less than 20% have Crohn’s disease.
  • Conversely, only 2.5 to 7.5% of patients with UC have or will develop PSC.
  • The true prevalence is likely much higher, but because many patients with UC are asymptomatic and show only minimal elevation in liver enzymes, cholangiography is not performed and they may remain undiagnosed.

Many other disorders, particularly inflammatory disorders, show an association with PSC. These include

  • hypereosinophilic syndrome,
  • Sjögren’s syndrome,
  • systemic sclerosis,
  • celiac disease,
  • pancreatitis,
  • Behçet’s syndrome,
  • histiocytosis X,
  • sarcoidosis,
  • sicca complex,
  • rheumatoid arthritis,
  • systemic mastocytosis,
  • histiocytosis X, and
  • Reidel’s thyroiditis.
The cause of PSC is unknown, and multiple mechanisms are likely to play a role.
  • The tight association between PSC and UC (a known autoimmune disease) suggests an autoimmune process. However, other mechanisms are likely to be important since only a minority of patients with UC have PSC.
  • An inflammatory reaction in the liver and bile ducts may be induced by chronic or recurrent entry of bacteria into the portal circulation. Liver damage may also result from the accumulation of toxic bile acids that are abnormally produced by colonic bacteria or chronic viral infection.
  • Ischemic damage to the bile ducts may occur.
Although the relationship between PSC and UC suggests a possible common pathogenesis, the two disorders may occur at different times. PSC may develop years after colectomy for UC, and UC may first present after liver transplantation has been performed for PSC.

Given the close association of PSC with ulcerative colitis, early investigators postulated that recurrent portal bacteremia might be an important factor in the development of the disorder.

  • Recurrent portal infection could lead to chronic biliary tract infection, inflammation, and subsequent fibrosis and classical stricture formation.
  • One study even found that portal bacteremia was present in patients who had colonic surgery.
  • Subsequent studies, however, could not confirm the findings of portal vein phlebitis.
  • Furthermore, 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.
  • 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.
  • 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.
  • 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.
  • Other toxic substances that have been considered more recently are N-formylated chemotactic peptides,
    • produced by enteric flora,
    • which have been shown in animal studies to induce fibrosis and damage to major bile ducts through colonic absorption and enterohepatic circulation.
    • Increased biliary excretion of these peptides has been shown in experimentally induced colitis in animal models.
    • Further investigation to delineate the role of these peptides in the etiology of PSC is required.

The major criticism of the theories of colonic toxins causing 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.
  • Furthermore, patients who have a colectomy show no change in their PSC natural history.
  • Some patients develop PSC years after a colectomy or even prior to the onset of their colitis.
  • Some patients who develop PSC never even have inflammatory bowel disease.
Antibiotics (which could, theoretically, alter the colonic flora) appear to have little effect on the natural history of PSC. 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 interesting 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.

Abnormalities of copper metabolism have also been implicated 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.
  • However,unlike other disorders with excessive copper deposition, treatment with chelating agents (penicillamine), has not been shown to have any benefit.
  • 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.

Chronic infection of the biliary tree has been implicated in the pathogenesis of PSC through several observations.

  • Longmire,who noted that some patients appear to develop PSC after an initial episode of acute necrotizing cholangitis, classified this group as a separate category (type 2) of PSC.

Patients with acquired immunodeficiency syndrome (AIDS) have been noted to have a sclerosing cholangitis that is 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.
  • Although reversibility of sclerosing disease in an infectious environment has been demonstrated in immunocompromised patients who have the underlying infection treated, this has not been demonstrated in normal hosts who have a fully functional immune system.
Experimental cholangitis and biliary atresia can be induced in animal models through infection with Reovirus type 3.
  • Early reports suggested that patients with PSC had a significant increase in antibody titers to this virus compared to controls.
  • More recent data, however, show no difference in prevalence or titers of Reovirus between controls and PSC patients.

Rubella can also cause an obliterative cholangitis of the intrahepatic ducts in the fetus, although the histological picture differs from that of PSC. Despite these negative studies, an infectious etiological agent that alters antigenic determinants has yet to be excluded in PSC.

Immune activation

There are multiple lines of evidence supporting an immunopathogenic cause for PSC. A number of abnormalities in humoral immunity have been described in these patients:

  • Up to 50 percent have an elevated IgM level, and some may also have an increased IgG fraction.
  • Autoantibodies are frequently present in patients with PSC, with titers in the range associated with autoimmune hepatitis. The most common are antismooth muscle antibodies and antinuclear antibodies, which are found in approximately 75 percent of patients
  • Antibodies directed against cytoplasmic and nuclear antigens of neutrophils with a characteristic perinuclear staining pattern (P-ANCA) are found in up to 80 percent of adults with PSC.
  • The antibodies appear to be directed against a myeloid 50 kilodalton nuclear envelope protein, not myeloperoxidase as in typical P-ANCA antibodies. In one report, P-ANCA had a 100 percent specificity for PSC compared to controls with other liver diseases; P-ANCA is also found in 25 to 30 percent of unaffected first degree family members of patients with PSC. P-ANCA has also been identified in children with PSC but not in those with UC alone.
  • These antibodies are not related to the presence or absence of UC.

Abnormalities of the cellular immune response have also been described in patients with PSC:

  • There are conflicting data reporting either an increase or decrease in the total number of circulating T cells; however, the number of CD4 positive T-cells in the liver is increased.
  • Bile duct epithelial cells in PSC may be targets for immune-mediated attack by T cells.
  • The bile duct cells in PSC express antigens which cross-react with colonic epithelial cells.
  • Bile duct cells aberrantly express HLA class II antigens, and ICAM (intercellular adhesion molecule)-1 is expressed by ductular epithelial cells.
Genetic factors
  • There may be a genetic predisposition to PSC since these patients have an increased prevalence of HLA-B8, -DR3, and -DRw52a .
  • One study, for example found that HLA DRw52a was present in 100 percent of patients with PSC.
  • Subsequent reports, however, have only found a 50 percent prevalence of this haplotype.
  • Both HLA-DRw52a and -DR4, which occurs less frequently, appear to increase the risk for severe or progressive disease.

Ischemic ductal injury

  • Ischemic injury to the bile ducts results in a clinical, biochemical, and cholangiographic picture similar to PSC.
  • Intraarterial infusion of floxuridine also results in a comparable appearance.
  • Thus, it is possible that ischemic injury to peribiliary arterioles and capillaries may be involved in the pathogenesis of PSC.
  • However, there are no data to support this hypothesis, or to demonstrate that hepatic or biliary blood flow is deficient in patients with this disorder.

Cystic fibrosis transmembrane conductance regulator mutations

  • Because of the radiologic and histologic similarities between PSC and cystic fibrosis, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been sought in patients with PSC.
  • One preliminary study suggested that a subset of patients with PSC had evidence of CFTR-mediated ion transport dysfunction; affected patients had a chloride secretory response intermediate between patients with cystic fibrosis and controls.

No comments: