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
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.
- 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.
- 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.
- 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.
- However, these findings are not specific, being commonly found in patients who have other forms of chronic cholestatic liver disease.
- Copper accumulation worsens as the disease progresses.
- However, these findings are not specific, being commonly found in patients who have other forms of chronic cholestatic liver disease.
- 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
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.
- 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
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 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, 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).
- 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.
- In contrast, bone mineral density in group 2 was not significantly different from controls, and no patient was below the fracture threshold.
- 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.
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.
- 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.
- 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.
- 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.
- 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.
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Please stop posting totally off-topic messages to the usenet group alt.comp.editors.batch
Klaus Meinhard
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