Wong Kam Punk’s Blog

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease
of the liver and bile ducts that is frequently progressive and can lead to end-stage liver disease. The disease is characterized by progressive inflammation, fibrosis, and stricturing of the intrahepatic and extrahepatic bile ducts. In the first part, epidemiology, classification and etiology has been discussed:

INTRODUCTION
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.

EPIDEMIOLOGY
* 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.

Gender —
* 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.

CLASSIFICATION
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

o primary (of unknown etiology) and
o 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
Intrahepatic
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

Extrahepatic
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.

PATHOGENESIS —
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.

o 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.

o Unfortunately, abnormalities in bile acid metabolism in PSC or UC
patients have not been demonstrated.
o 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,

o produced by enteric flora,
o which have been shown in animal studies to induce fibrosis and
damage to major bile ducts through colonic absorption and enterohepatic circulation.
o Increased biliary excretion of these peptides has been shown in
experimentally induced colitis in animal models.
o 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 cold, 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 immuno deficiency 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.

Dr. Jitendra Agrawal, Kanpur, India.

The majority of patients with primary sclerosing cholangitis are
asymptomatic at the time of diagnosis, although some may have advanced disease. The disease should be considered in patients with
inflammatory bowel disease who have otherwise unexplained abnormal
liver biochemical tests, particularly an elevation in serum alkaline
phosphatase. A review of clinical manifestation, diagnosis and
differential diagnosis has been discussed:

Continued destruction of bile ducts in PSC leads to end-stage liver disease and portal hypertension. Patients with PSC also may develop a number of other complications, including:

* Cholestasis-associated problems
* Biliary stricture
* Cholangitis and cholelithiasis
* Cholangiocarcinoma
* Colon cancer

Clinical manifestations
PSC predominantly affects males, with a median onset of 40 years of age but a wide range of 1 to 90 years. Pediatric cases show an increased association with immunodeficiency states (10%) and histiocytosis X (15%), and a lesser association with inflammatory bowel disease (47%). The male predominance occurs primarily in patients with both PSC and ulcerative colitis.

Clinical presentation of primary sclerosing cholangitis.
Source: Ludwig et al.
Symptom Percent of presentation
Jaundice 75–80
Right upper quadrant pain 50–55
Pruritus 30–35
Fever 20–25
Weight loss 15–20
Fatigue 10–15
Asymptomatic 5–10

* PSC has been reported in all races.
* The disorder tends to develop insidiously, with symptoms present in one study for a mean of 52 months (range 0– 451 months) prior to diagnosis.
* Symptoms of PSC are often nonspecific initially, but jaundice, right upper quadrant pain, pruritis, fever, weight loss, and fatigue subsequently develop.
* Atypical presentations of fever of unknown origin or acute supportive cholangitis have been reported.
* Periodic exacerbations and remissions are typical of the disorder.

o Exacerbations may be precipitated by gallstones, which form in a
strictured biliary tree where normal flow is impeded.
* Depending on the location of the stones and the strictures, endoscopic or percutaneous treatment can be useful in removing a nidus of recurrent infection.
* Unfortunately, many strictures and stones develop in the proximal biliary tree, which may be less amenable to mechanical intervention.
* An association with other autoimmune disorders has been noted in patients with PSC.
* More recently, an association with celiac disease has also been
documented.

With the increased awareness of PSC, availability of ERCP, and use of laboratory screening, more patients who have asymptomatic elevations in liver enzymes are being diagnosed with this disorder, particularly if they have underlying ulcerative colitis.

* In particular, asymptomatic elevations of alkaline phosphatase in the
setting of chronic ulcerative colitis should raise the suspicion of sclerosing cholangitis and trigger further investigation.

Early in the course of PSC, the physical examination is normal.

* As the disease progresses, physical stigmata of chronic liver disease
(spider angioma, jaundice, palmar erythema) and hepatosplenomegaly may become apparent, as well as the development of portal hypertension, resulting in ascites and varices.

Laboratory evaluations
Elevation of cholestatic liver enzymes is typical of this disease.

* Up to 98% of patients will have an increase in the alkaline phosphatase level, although normal alkaline phosphatase levels have occasionally been recorded, even in symptomatic patients.
* Most often, the serum alkaline phosphatase is at least twice the upper limit of normal, out of proportion to that of the serum bilirubin.
* Serum bilirubin levels are also variable (especially early in the course
of the disease) but inevitably, as the disease progresses, elevations occur in conjunction with a gradual decline in serum albumin.
* Caution must be used in interpreting isolated findings of low albumin as a negative prognostic factor in PSC, as it may also be decreased by active inflammatory bowel disease in many patients.
* Transient worsening of serum transaminases and bilirubin often occurs during exacerbations of the disease.
* These will often return to near normal when the episode of fever, chills,or right upper quadrant pain has resolved.

Additional serologic findings in patients with PSC include:

* Hypergammaglobulinemia — 30 percent
* Increased serum IgM levels — 40 to 50 percent
* Atypical perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) — 30 to 80 percent
* Human leukocyte antigen DRw52a — 0 to 100 percent in various reports.

Antimitochondrial antibodies, which are characteristic of primary biliary
cirrhosis, are usually absent in PSC

* The presence of autoantibodies did not correlate with disease severity,with the exception of anticardiolipin antibodies, which correlated with the Mayo risk score.
* Interestingly, elevated serum IgG4 (a marker of autoimmune pancreatitis) has been described in up to 9 percent of patients with PSC.
* Hepatic and urinary copper levels are increased and serum ceruloplasmin is reduced in most patients with PSC.

o However, these findings are not specific, being commonly found in
patients who have other forms of chronic cholestatic liver disease.
o Copper accumulation worsens as the disease progresses.

DIAGNOSIS
* The diagnosis of PSC is established by the demonstration of characteristic multifocal stricturing and dilation of intrahepatic and/or extrahepatic bile ducts on cholangiography.
* Abnormal bile ducts may also be suggested on ultrasound, although findings are usually not diagnostic.
* Magnetic resonance cholangiography may be an alternative to endoscopic cholangiography, particularly if the image quality continues to improve.

The biliary strictures may be focal, with normal intervening areas, or diffuse and involve a long segment. Strictures can occur in any part of the biliary tree. In one report of 100 patients, strictures were present in the following distribution:

* Intrahepatic and extrahepatic bile ducts — 87 percent
* Intrahepatic bile ducts alone — 11 percent
* Extrahepatic bile ducts alone — 2 percent

The gallbladder and cystic duct may also be involved.

An ERC in patients with PSC is not without risk; a complication rate of up to 14% has been documented.

* In particular, cholangitis can occur, presumably because focal areas of the biliary tree are poorly drained, resulting in biliary stasis.
* Since an ERC catheter is not sterile, infection of the biliary tree
following an ERC is not uncommon.
* To decrease this risk, all patients with suspected PSC should receive
broad-spectrum antibiotics prior to the procedure.
* Those who have been demonstrated at ERC to have PSC should receive several days of antibiotics postprocedure.
* Since most ERCs are done as daycare procedures, an oral antibiotic is preferable, although parenteral antibiotics can easily be administered prior to the procedure.
* Ciprofloxacin is effective against most of the typical biliary pathogens.

In contrast to the characteristic strictures, shallow ulcerations of the bile ducts may be the only cholangiographic finding in patients with early stage disease.

* In addition, cholangiography is normal in a small percentage of patients who have a variant of PSC known as “small-duct primary sclerosing cholangitis.”
* This variant (sometimes referred to as “pericholangitis”) is probably a
form of PSC involving small caliber bile ducts.
* It has similar biochemical and histologic features to classic PSC. It
appears to have a significantly better prognosis than classic PSC, although it may evolve into classic PSC.
* Classic PSC developed in only 4 of 27 patients in one series that focused on 27 of 32 patients with small-duct PSC who had undergone repeated cholangiographic examinations after a median of 72 month.
* Pancreatograms have been noted to be abnormal in up to 10% of PSC patients. Stricturing or tapering of the pancreatic duct was noted in 3/40 patients with PSC in the Mayo series.
* An unusual amount of pancreatic duct reflux was noted in 43% of patients and overall pancreatic duct abnormalities in up to 50% of patients.

Differential diagnosis —
Secondary causes of the cholangiographic findings described above should be considered. These include

* chronic bacterial cholangitis,
* infectious or ischemic cholangiopathy, and
* malignancy.

A rare, steroid-responsive disorder involving stricturing of the
pancreaticobiliary tract and elevated serum levels of IgG4 has been described that shares clinical and radiographic features with PSC.

* This disorder has been referred to as sclerosing pancreatocholangitis,autoimmune pancreatitis, and immunoglobulin G4 associated cholangitis.
* Some authorities suggest that serum IgG4 be measured in all newly
diagnosed patients with PSC.
* Corticosteroids can given to those with clinical, biochemical and imaging features of immunoglobulin G4 associated cholangitis provided that a response can be assessed on imaging and liver biochemistries.

Liver biopsy —
A percutaneous liver biopsy may support the diagnosis of PSC, but is rarely diagnostic.

* The most specific histologic finding in PSC is fibrous obliteration of
small bile ducts, with concentric replacement by connective tissue in an “onion skin” pattern.
* More often, histologic abnormalities in PSC are nonspecific and are
similar to those in primary biliary cirrhosis.

* The histologic findings initially involve the portal triads, but expand
into the hepatic parenchyma as the disease progresses.
* As a result, liver biopsy is helpful for staging the disease and
determining prognosis.

The staging system used most commonly in PSC is similar to that used in primary biliary cirrhosis:

* Stage I — Enlargement, edema, and scarring of the portal triads, and mononuclear cell infiltration with some piecemeal necrosis and damage to isolated bile ducts. Proliferation of interlobular bile ducts with mononuclear and polymorphonuclear cells may also be present, although the inflammation is usually less dense than in primary biliary cirrhosis.

* Stage II — Expansion of portal triads with fibrosis extending into the
surrounding parenchyma

* Stage III — Bridging fibrosis

* Stage IV — Cirrhosis

Liver biopsies are not routinely recommended following a diagnostic
cholangiogram.

PROGNOSIS —

* PSC is usually a progressive disorder that ultimately leads to
complications of cholestasis and hepatic failure.
* Median survival without liver transplantation after diagnosis is 10 to 12 years.
* Survival is significantly worse for patients who are symptomatic at the time of diagnosis.

Several groups have studied variables that appear to predict prognosis in PSC.
These include age, histological stage, hepatomegaly, splenomegaly, serum alkaline phosphatase, and serum bilirubin.

One study, for example, found that approximately 90 percent of those with stage II disease would be expected to progress to bridging fibrosis or cirrhosis while approximately one-half of those who had already developed bridging fibrosis were expected to develop cirrhosis within five years. This was a predicted progression based on their model.
Variables associated with prognosis have been incorporated in a well-validated statistical model (the Mayo risk score.

* The components of the Mayo risk score include age, serum bilirubin, serum albumin, serum AST, and history of variceal bleeding.
* The calculation of this risk score correlates well with observed survival and is useful in assessing prognosis and determining timing for liver transplantation.

CHOLESTASIS —
The complications common to all of the chronic cholestatic liver diseases such as PSC include fatigue, pruritus, steatorrhea, fat-soluble vitamin deficiencies (A, D, E, and K), and metabolic bone disease. Little is known about the pathogenesis of fatigue; nevertheless, it may become quite debilitating, and is one of the prime indications for liver transplantation.

Pruritus —
Pruritus is a common symptom of PSC which can be extremely disabling, leading to severe excoriations and a decreased quality of life.

* The pathogenesis of pruritus in PSC, as in other disorders which cause cholestasis, is not clear. Several hypotheses have been proposed, including bile acid accumulation and endogenous opioids.
* Treatment should be based upon the severity of the pruritus.

Steatorrhea and vitamin deficiency —
* Steatorrhea with concomitant fat soluble vitamin deficiency in patients
with PSC is generally thought to be due to decreased secretion of conjugated bile acids into the small intestine.
* However, associated conditions that may coexist with PSC, such as chronic pancreatitis and celiac disease, may also contribute to the genesis of steatorrhea; these disorders should be considered in the differential diagnosis of steatorrhea in a patient with PSC who has no jaundice or evidence of cirrhosis by histology.

* Vitamin A deficiency has been reported in up to 82 percent of patients with advanced PSC, occasionally accompanied by night blindness.
* In addition, vitamin D and vitamin E deficiencies occur in approximately one-half of those with advanced disease.
* Thus, patients with PSC should be screened for fat soluble vitamin
deficiencies by determination of the prothrombin time (vitamin K) and serum levels of vitamins A, D, and E.
* Supplemental therapy should be administered as necessary.

Metabolic bone disease —
* Metabolic bone disease, in particular osteoporosis, is a complication of advanced PSC, with radiologic and histologic evidence of osteopenia in the lumbar spine, iliac crest, and femur.
* An illustrative study found that 38 percent of patients with PSC had a bone density more than three standard deviations below the mean in the lower lumbar spine and the femoral neck on dual photon absorptiometry.
* In a second report, bone density was measured in 30 patients with advanced PSC (group1) and 18 patients with newly diagnosed disease (group 2).

o Mean bone mineral density was significantly reduced in group 1
compared with age-matched and sex-matched controls (0.97 versus 1.25 gm/cm2); in 15 of the 30 patients, bone density was below the fracture threshold.
o In contrast, bone mineral density in group 2 was not significantly
different from controls, and no patient was below the fracture threshold.

Patients with PSC are also prone to develop fractures after liver
transplantation, even in the absence of metabolic bone disease, due to immobilization and concomitant therapy with Corticosteroids.

* The pathogenesis of bone disease in PSC and other chronic cholestatic liver diseases (eg, primary biliary cirrhosis) is unknown.
* Bone disease in patients with PSC is due to osteopenia/osteoporosis rather than osteomalacia, and thus, malabsorption of vitamin D,

slow serum vitamin D concentration is not the cause in most cases.

Furthermore, vitamin repletion in the minority of cases with low serum
levels does not reduce either the presence or severity of osteoporosis.

Radiologic techniques such as dual photon absorptiometry are superior to traditional serum and urinary markers of bone loss for diagnosing osteopenia in patients with PSC. The axial skeleton (eg, trabecular bone of the lumbar spine) is affected more commonly than the appendicular skeleton (cortical bone).

Although few studies have specifically addressed the treatment of bone disease in PSC, management principles are similar to those in primary biliary cirrhosis. Calcium supplementation and measurement of vitamin D levels are generally recommended.

* For patients with more significant loss of bone density, bisphosphonate therapy may also be beneficial.

DOMINANT BILIARY STRICTURES —
* Approximately 20 percent of patients with PSC develop a dominant stricture in the intrahepatic or extrahepatic biliary tree.
* Strictures can occur at the biliary hilum or anywhere along the common hepatic or common bile ducts.
* Patients typically present with evidence of mechanical biliary obstruction manifested by jaundice, pruritus, ascending cholangitis, and malabsorption.
* This presentation is difficult to distinguish from that of
cholangiocarcinoma.
* Thus, if a dominant stricture is identified, cytologic brushings of the
stricture should be performed to exclude malignancy.

Medical therapy to treat biliary strictures has been ineffective. Nonsurgical modalities to relieve biliary obstruction, such as endoscopically or radiologically guided balloon dilation of strictures or placement of prosthetic stents across strictures, should be attempted initially.

CHOLANGITIS AND CHOLELITHIASIS —
* Choledocholithiasis and cholelithiasis, due to cholesterol and/or pigment stones, may be present in up to one-third of patients with PSC.
* Ultrasonography can identify biliary obstruction but has a low sensitivity for determining its cause (eg, stricture, stone, or neoplasm).
* Thus, cholangiography should be used to detect reversible causes of
biliary obstruction.

Gallstones in patients with PSC are treated the same way as in other patients.

* are made to remove gallstones only if they are causing obstruction of the major bile ducts; incidental gallstones in the gallbladder are not treated unless the clinical scenario dictates that they need to be removed.

Bacterial cholangitis can occur in patients with PSC.
* The risk is greatest after endoscopic or surgical manipulation (including liver biopsy), but cholangitis can also develop spontaneously, particularly in patients with bile duct stones or obstructing strictures. Biliary candida infections have also been described.

CHOLANGIOCARCINOMA —
* Patients with PSC have a 10 to 15 percent lifetime risk of developing
cholangiocarcinoma; those with inflammatory bowel disease and cirrhosis may be at highest risk.
* In one series, the only independent risk factor for development of
cholangiocarcinoma in patients with PSC was variceal bleeding.

* The annual incidence of cholangiocarcinoma developing in the setting of PSC has been estimated to be 1.5 percent.
* In a series of 161 patients seen at the Mayo clinic, 7 percent developed cholangiocarcinoma during a mean follow-up of 11.5 years.
* The development of cholangiocarcinoma is often heralded by rapid clinical deterioration with jaundice, weight loss, and abdominal discomfort.
* The presence of progressive biliary dilatation in the setting of a
dominant stricture should also raise a strong suspicion of cholangiocarcinoma.

Why patients with PSC develop cholangiocarcinoma is not well understood.

* A case-control study compared 20 patients with PSC and hepatobiliary carcinoma (17 cholangiocarcinoma, 2 hepatocellular carcinoma, 1 gallbladder carcinoma) to 20 age- and sex-matched patients with PSC without cancer.
* No clinical or biochemical risk factors for the development of cancer
could be identified in the year before cancer diagnosis.
* In another case-control trial, the risk was increased by regular alcohol consumption.

Diagnosis and screening —
* The diagnosis of cholangiocarcinoma can be extremely difficult in patients with PSC.
* In an illustrative study, 10 percent of patients with PSC undergoing liver transplantation had an unsuspected cholangiocarcinoma.
* Delayed diagnosis often results in the discovery of tumors at an advanced stage when they cannot be resected for cure.
* As previously mentioned, it is also difficult to distinguish a dominant
stricture from a cholangiocarcinoma, even with imaging, endoscopic biopsy, and cytology.

The tests used to make the diagnosis include biliary brush cytology, endobiliary biopsy, CT or MRI scanning, and serum tumor markers such as CEA or CA 19-9.

* However, all of these studies have limitations while none has proven to be beneficial for screening.
* It is not recommended to do routine screening for cholangiocarcinoma in patients with PSC.
* No studies have been performed that demonstrate a benefit in patient outcomes with screening using serum tumor markers, imaging studies, or cholangiographic brush cytology.

Prognosis — The presence of cholangiocarcinoma portends a poor prognosis in patients with advanced PSC; only 10 percent of patients survived two years in one report.

* Liver transplantation has been a disappointment in the treatment of
cholangiocarcinoma, with significantly lower patient survival due to recurrent disease.
* Thus, most transplant centers are not transplanting these patients outside of study protocols.
* The poor prognosis has led to the suggestion for earlier liver
transplantation in patients with PSC before cholangiocarcinoma has a chance to develop.

COLON CANCER —
* Patients with both PSC and ulcerative colitis have an increased risk of colon cancer and progression of neoplastic transformation.

Based upon these data, it would seem appropriate to perform frequent
colonoscopic surveillance with multiple biopsies every 10 cm in the colon to screen for dysplasia in patients with PSC and ulcerative colitis. Surveillance colonoscopy should begin once a diagnosis of ulcerative colitis is established in a patient with PSC.

Dr. Jitendra Agrawal, Kanpur, India.