Of critical importance is understanding a fundamental difference between sclerotic biliary tract disorders and disorders of a hepatocellular nature. Hepatocytes have a remarkable ability to regenerate, and, when the inciting agent (i.e. fulminant viral hepatitis) is removed, treated, or spontaneously disappears, patients can fully recover despite a major insult.
- On the other hand, when patients with PSC (or other sclerotic biliary disorders) scar their biliary tree, this results in a permanent loss of function with limited ability for regeneration.
- Once the serum bilirubin starts to rise, a seemingly irreversible, medically untreatable disorder is present and liver transplantation is the only viable, long-term alternative.
Ideally, medical therapy should be directed at the underlying cause of PSC (but this is unknown) and administered early in the course of the disease when the patient is asymptomatic, which is not always possible.
- Although a variety of antifibrotic, anti-inflammatory, and immunosuppressive medications have been used to treat PSC, none of them has shone effectiveness in altering the natural history of the disease.
Treatment of the disorder is therefore divided into
- medical therapy for PSC,
- symptom control,
- complication therapy, and
- monitoring for malignancy
Medical treatments evaluated in primary sclerosing cholangitis.
- Ursodeoxycholic acid (UDCA)
- Methotrexate
- Azathioprine
- Cyclosporine
- Corticosteroids
- Colchicine
- Cholestyramine
- Antibiotics
Ursodeoxycholic acid (UDCA)
- (UDCA), a hydrophilic bile acid, is the most extensively studied of all medical treatments for PSC.
- UDCA, at a dose up to 15 mg/kg/d is thought to exert its effects in cholestatic conditions via
- protection of cholangiocytes against cytotoxic hydrophobic bile acids,
- stimulation of hepatobiliary secretion,
- protection of hepatocytes against bile-acid induced apoptosis, and induction of antioxidants.
- Although the standard dosages of UDCA (10 to 15 mg/kg) have been used in most studies, if biliary enrichment of UDCA represents the decisive factor for its clinical effect, it seems likely that UDCA doses of up to 22 to 25 mg/kg may be more effective than lower doses.
- UDCA may have an immunologic effect by decreasing the expression of Class 1 antigens, and a choleretic effect by increasing bile flow.
- Numerous uncontrolled trials demonstrated a beneficial effect (primarily biochemically with improvement of alkaline phosphatase).
- Symptom improvement was variable and liver histology usually not available.
- In one study UDCA was associated with improvement in serum alkaline phosphatase, aspartate aminotransferase, bilirubin, and albumin concentrations at one and two years, but there was no significant difference between the groups in time to treatment failure or liver transplantation.
- Similarly, UDCA is not able to prevent the development of biliary strictures.
- A derivative of UDCA (24-norursodeoxycholic acid) has shown promise in an animal model of PSC.
- In a more recently presented abstract, the combination of UDCA with metronidazole in a randomized sample of 80 patients resulted in improved histology and New Mayo Risk Scores in patients in the combined group over a period of 3 years. The theory in this study is that the antibiotic may have activity against anaerobes and thereby decrease anaerobic bacteria within the biliary tree.
From these studies, it can be concluded that there is a beneficial effect of UDCA on serum transaminases and alkaline phosphatase; unfortunately, it does not appear to improve hepatic histology or symptoms or prolong survival, evolution of cirrhosis, or time to transplantation.
Recently, a study of 52 PSC/UC patients were assigned to UDCA had a relative risk of 0.26 for developing colorectal dysplasia or cancer (95% confidence interval, 0.06–0.92; P 0.034) versus a control group. UDCA therefore, significantly decreases the risk for developing colorectal dysplasia or cancer in patients with UC and PSC.
Corticosteroids —
No studies to date have demonstrated a long-term benefit from corticosteroid therapy, either alone or in combination with agents such as colchicines.
- As an example, a trial in which hydrocortisone was applied topically to the biliary tree via lavage with a nasobiliary tube resulted in worsening of liver function tests and also led to cholangitis and septicemia in some patients.
- Systemic corticosteroid have also been associated with enhanced loss of trabecular bone, which leads to an increased risk of osteoporosis and spinal compression fractures.
- This has been confirmed in a randomized trial from
- Unfortunately, when the authors performed a prospective double-blind randomized control trial (methotrexate 15 mg/week versus placebo) in 24 patients with PSC, the only significant change was a fall (31%) in the serum alkaline phosphatase in those receiving methotrexate.
- There was no improvement in symptoms, histology, serum albumin, bilirubin, or transaminases.
- Complications of methotrexate were minimal, with only a single episode reported of Campylobacter enterocolitis and one leukopenic episode related to bacterial cholangitis.
- Since many patients in this study had advanced disease (7/12 receiving methotrexate had cirrhosis), it is possible that a positive effect in early-stage PSC could have been missed.
- Unfortunately, given its toxicity such as pulmonary fibrosis and hair loss, and the lack of benefit of methotrexate added to ursodeoxycholic acid (UDCA) in 19 patients with PSC by Lindor et al., it is unlikely that a larger trial can be justified.
D-PENICILLAMINE
Since hepatic copper levels are increased in all patients with cholestatic liver disorders, penicillamine was tested in a well-designed, randomized, placebo-controlled trial of 70 patients at the Mayo Clinic.
- As expected, urinary excretion of copper increased with concomitant reduction in hepatic copper concentrations; however, after 3 years there were no beneficial effects on symptoms, biochemical results, liver histology, disease progression, or survival.
- In addition, significant toxicity, such as proteinuria and pancytopenia, leading to permanent discontinuation of penicillamine, was noted in 21% of patients, thereby discouraging any further use of this agent in PSC.
IMMUNOSUPPRESSIVE THERAPY
Other immunosuppressive drugs have been tried in a number of studies. No controlled trials are available for azathioprine but in one uncontrolled study two patients improved, while in the other case report the patient deteriorated.
Cyclosporine —
- Aside from a decrease in serum alkaline phosphatase in treated patients, there was no effect upon symptoms or disease progression.
- A case report noted radiologic and biochemical improvement after treatment with cyclosporine followed by prednisolone; however, the patient was also given ursodeoxycholic acid concomitantly, and follow-up was unavailable after eight months.
- In another study Cyclosporine has been used in a randomized clinical trial involving 34 patients with PSC, most with coexisting ulcerative colitis. After 2 years of therapy, the ulcerative colitis had improved but there was no beneficial effect demonstrated on serum hepatic biochemistry.
Tacrolimus (FK-506) has been used in one open study in10 patients with PSC.
- After 360 days, there was evidence of biochemical improvement in all patients. A randomized controlled clinical trial is required to confirm these results.
- Although there was some improvement in pruritis, there was no improvement in biochemical parameters.
- Recently, 30 patients underwent a 1-year trial with mycophenolate mofetil with no significant clinical or biochemical improvements.
MANAGEMENT OF COMPLICATIONS OF PSC
Associated complications of PSC include fatigue, pruritus, steatorrhea, fat soluble vitamin deficiency and its complications, including osteoporosis.
Fatigue often parallels progression of disease and can be disabling; however, no medical treatment has been demonstrated to be effective in ameliorating this symptom.
Pruritus can be intense, leading to a diminished quality of life as well as skin and systemic infections arising from excoriations.
- The pathogenesis of itching may be related to the increased availability of endogenous opiate ligands at central receptors.
- Although therapy for pruritus associated with cholestatic liver diseases typically is initiated with cholestyramine, other medical therapies include activated charcoal, rifampicin, phenobarbitol, plasmapheresis, and opiate antagonists (naloxone, nalmefene).
- Cholestyramine is a nonabsorbable resin that binds bile acids and therefore results in increased fecal excretion of bile by inhibiting enterohepatic circulation.
- The dose is typically 12 to 24 g/day, but since over 50% of patients receiving the drug are troubled by constipation and nausea, compliance is often poor.
- The dose is typically 12 to 24 g/day, but since over 50% of patients receiving the drug are troubled by constipation and nausea, compliance is often poor.
- In primary biliary cirrhosis, rifampicin has been demonstrated to be more effective in reducing pruritus than phenobarbital.
- Unfortunately, up to 10% of patients develop drug-induced hepatitis from rifampicin, necessitating discontinuation of this medication.
- Opiate antagonists such as naloxone are occasionally useful in ameliorating pruritus but they are awkward to use and can be expensive.
- A more recent attempt at extracorporeal albumin dialysis in a single case was met with some improvement in biochemical parameters as well as pruritis.
Cholestasis eventually results in significant changes in fat malabsorption.
- Although chronic pancreatitis and celiac disease have been associated with PSC and can contribute to fat malabsorption, most patients with PSC have steatorrhea secondary to decreased bile acid concentrations within the small intestine.
- Fat-soluble vitamins (A, D, E, and K) are typically malabsorbed and patients can occasionally develop night blindness, osteomalacia, and coagulopathy.
- Patients should be screened for these deficiencies and supplemental therapy supplied as required.
Osteoporosis is a common problem in cholestatic liver disease.
- In 50% of PSC patients undergoing transplantation, the bone density levels are below the fracture threshold.
- One third of liver transplant patients with PSC will develop vertebral compression fractures.
- Bone mineral densities do not correlate with serum bilirubin (or the severity of liver disease) or 25-hydroxyvitamin D, fecal fat, or the presence or absence of ulcerative colitis.
- As in primary biliary cirrhosis (PBC), the etiology of the osteoporosis is unknown and therapy has not been fully evaluated.
- Dual-energy Xray absorptiometry and dual-photon absorptiometry are noninvasive techniques that provide an excellent quantification of the bone mass.
- Antiresorptive agents such as the biphosphonates (etidronate, pamidronate, alendronate) may avoid the osteopenic complications but further clinical trials in this area are necessary.
The end stages of PSC are often associated with portal hypertension resulting in esophageal varices, ascites, and encephalopathy.
These complications can be managed in the usual fashion for patients with end-stage liver disease, with a few exceptions.
- It has been demonstrated that 36% of patients with PSC will have esophageal varices and that a suppressed platelet count, advanced histological stage, and low albumin levels are all predictors of the presence of esophageal varices.
- These patients should be targeted for endoscopic variceal screening protocols.
- Particular caution should be maintained in patients being considered for systemic surgical shunting for difficult to control esophageal or gastric varices.
A troublesome complication of portal hypertension that occurs in those patients who have undergone proctocolectomy is bleeding from peristomal varices.
- This bleeding can be severe with therapy of sclerosants only providing temporary relief.
- TIPS or surgical portosystemic shunts can control bleeding, but since most of these patients have severe portal hypertension, liver transplantation should always be considered.
A recently recognized complication of PSC patients with a history of colitis is a substantially increased risk of colon cancer.
- This risk appears to start relatively early in their course and continues even after liver transplantation (risk of colorectal cancer 10 to 14% at 5 years post-transplant).
- Aggressive endoscopic surveillance is recommended.
ENDOSCOPIC MANAGEMENT OF PSC
Although bacterial cholangitis is an unusual presentation of PSC, once the biliary tree has been manipulated (either percutaneously, endoscopically, or surgically) it becomes colonized, typically with Gram-negative organisms, and recurrent biliary sepsis is common.
- If “dominant” strictures are present, several major endoscopy centers have demonstrated that endoscopic therapy is successful in relieving sepsis and improving biochemical tests.
- In 1987, the
- In those with high-grade strictures, endoprostheses were inserted.
- Strictures treated endoscopically were typically at the level of the hilum or common bile or hepatic duct.
- The number of hospitalizations decreased from 2.5 to 0.2 per year and over a follow-up period of 19 months both the serum bilirubin and alkaline phosphatase decreased significantly from 6.9 to 2.7 mg/dL and 959 to 385 IU/L respectively.
- Three patients died; one from a cholangiocarcinoma, one from bleeding peristomal varices, and the last from an unknown cause.
- Only one complication of endoscopic therapy was noted in this series: a single case of mild pancreatitis.
- In those with high-grade strictures, endoprostheses were inserted.
Subsequently, Cotton et al. reported a 32% reduction in bilirubin levels and 29% reduction in alkaline phosphatase after a mean follow-up of 6 months in 17 PSC patients treated with a combination of endoscopic dilation, endoprosthesis, and biliary sphincterotomy.
In 1991, the
- They used a combination of dilating catheters and hydrostatic balloon dilators to dilate perceived dominant strictures.
- In addition, biliary stents were inserted in 11 patients who could not be adequately dilated.
- Typically, the stents were removed in 2 to 3 months and dilation performed during a second ERC.
- They demonstrated that the number of hospitalizations, total serum bilirubin, and average radiological stricture score all decreased significantly in patients treated endoscopically.
- Overall, 77% of patients had improvement in their clinical symptoms, liver function tests, or cholangiograms.
- From the patients’ point of view, of 50 patients available for evaluation, 28 felt better, 21 the same, and one felt worse following the therapeutic ERCP.
- These procedures are done with broad spectrum antibiotics before the ERC and for a minimum of 24 hours after the procedure.
- Dilating balloons are typically held in position for 30 to 60 seconds until the constricted “waist” is obliterated.
Predicting which patients may benefit from a therapeutic ERC is always difficult. A single large study to evaluate these predictors was performed and reviewed all patients at
- It demonstrated that those patients who underwent therapeutic procedures, had a dominant stricture (could be assessed pre-ERC with MRC to localize diseased segments), or were jaundiced had an increased rate of clinical/laboratory improvement following the procedure.
- First, as noted by Gaing et al. in 1993, approximately 50% of patients will have disease that is primarily intrahepatic in nature, thereby making it more difficult to treat endoscopically.
- With advancing radiological techniques such as magnetic resonance cholangiograms (MRC), it might be reasonable to consider screening patients with PSC with MRC to determine if there is disease that is amenable to endoscopic therapy.
- Providing that MRC is sensitive and specific for the location of endoscopically amenable strictures, it could avoid diagnostic ERCs in selected patients.
- Conceivably, even if, in theory, the lesions were amenable to endoscopic therapy the site and complexity of the procedure could be predicted (i.e. hilar strictures) and referral to a center with specialized ERCP expertise considered.
- Second, the complication rate following an ERC in a patient with PSC may be as high as 15%.
- This is primarily accounted for by ascending cholangitis. Pre- and postoperative antibiotic should be administered in all patients with known and suspected PSC to avoid this complication.
- This is primarily accounted for by ascending cholangitis. Pre- and postoperative antibiotic should be administered in all patients with known and suspected PSC to avoid this complication.
- Third, strictures in PSC must always be evaluated for the presence of malignancy.
- Even with aggressive brushing sampling, only a 50 to 60% sensitivity is obtained.
- A combination of serological tumor markers (e.g. CEA, CA19-9) with repeated brushings may increase the diagnostic yield of cholangiocarcinoma in this disease.
- Even with aggressive brushing sampling, only a 50 to 60% sensitivity is obtained.
- Finally, although there are reports of possible prolongation of survival with endoscopic therapy, convincing evidence of this, or increased survival or delaying transplantation, has not been demonstrated in most patients with PSC treated endoscopically.
- Additionally, more recently some authors have challenged the results of endoscopic series suggesting that at follow-up after endoscopic treatment of dominant strictures there is actually very little, if any, alteration in biliary biochemical parameters.
- Randomized trials have been suggested but are unlikely to be performed as, given that this is a relatively uncommon condition, a multicenter approach would be required and patients would be difficult to randomize to a “sham” arm of the study.
Recent investigators have looked at the use of nasobiliary lavage following endoscopic therapy.
- Wagner et al. followed 12 patients with dominant strictures from PSC treated with hydrostatic balloon dilation and nasobiliary drainage for up to 50 months.
- Eight patients demonstrated biochemical improvement with only three requiring liver transplantation.
- No major complications were reported.
Although the diagnostic potential of MRC may be great, the therapeutic role of ERC in PSC is unlikely to be replaced in the near future.
It must be remembered, however, that published results have been produced by experts at experienced biliary centers and these results may not be generalizable to smaller centers.
CHOLANGIOCARCINOMA
Up to 15% of patients with PSC may eventually develop cholangiocarcinoma.
- The patients at highest risk have traditionally been reported to be those with longstanding cirrhosis and ulcerative colitis.
- However, in a single study by Burak et al. the only clinical risk factor for cholangiocarcinoma in this patient population was a history of variceal bleeding (RR 24.2; 95%CI: 3.3–67.1).
- It would be logical to theorize that cholangiocarcinoma may be more common in those patients with dominant biliary strictures and one recent abstract has demonstrated a 20% malignancy rate over the 2 years following diagnosis of a dominant biliary stricture in a large series of PSC patients.
- Ultrasound and computed tomography (CT) have a low sensitivity for the diagnosis of primary bile duct tumors.
- The advent of duplex ultrasonography and bolus-enhanced CT scans may increase sensitivity up to 80%.
- Biliary brushings of the stricture have a variable yield of between 50 and 80%.
- In addition to technical factors regarding tissue sampling, the yield may be increased by careful attention to cytological classification systems.
- Tumor markers, such as serum CEA, have not been shown to be sensitive, with a sensitivity of only 53% being reported in one group of 15 patients with cholangiocarcinoma (11 occult tumors).
- Serum levels of Ca 19-9 appear to be slightly more sensitive and specific, although it has not been found to be predictive of cholangiocarcinoma in patients with advanced disease (the group thought most likely to develop this tumor).
- Ramage et al. have shown that the calculation of a serum tumor index (CEA . 40 + carbohydrate antigen (CA) 19-9) was 86% accurate in diagnosing cholangiocarcinoma in PSC patients and probably is the best laboratory-based method to raise suspicion of a malignant lesion.
- Biliary CEA, which can be detected through bile aspirates, also has been suggested as a possible marker for cholangiocarcinoma.
- Unfortunately, it is also elevated in patients with intrahepatic cholelithiasis, which is relatively common in PSC.
- Biliary CEA is also mildly elevated in PSC itself making its accuracy in assessing cholangiocarcinoma in PSC questionable.
- Unfortunately, it is also elevated in patients with intrahepatic cholelithiasis, which is relatively common in PSC.
- Biliary Mac-2BP levels were elevated by a factor of approximately three in the biliary carcinoma group compared with the group of patients who had PSC or another type of non-neoplastic biliary disease.
- Serum levels of Mac-2BP levels were not elevated in those patients with biliary tract cancers.
- According to the immunohistochemical analysis, Mac-2BP was expressed in 34 of 36 patients (94.4%) with biliary tract carcinoma.
- As a diagnostic marker for biliary carcinoma, Mac-2BP levels were as accurate as biliary CA19-9 levels; however, the use of both of these bile markers in combination led to significantly better diagnostic accuracy compared with the accuracy achieved using CA19-9 alone (area under the curre, 0.75; P < 0.001).
- It appears from this study that biliary Mac-2BP levels show promise as a novel diagnostic marker for biliary tract carcinoma.
- According to the immunohistochemical analysis, Mac-2BP was expressed in 34 of 36 patients (94.4%) with biliary tract carcinoma.
- However, in patients with the incidental finding of cholangiocarcinoma in the explanted liver (with regional lymph nodes clear of disease), long-term survival similar to those undergoing transplant without cholangiocarcinoma has been reported.
- Therefore, those patients who are diagnosed with cholangiocarcinoma preoperatively may be expected to have a poor prognosis; however, it has been reported that those with cholangiocarcinoma discovered incidentally may have a long survival.
- In other studies, however, even those with cholangiocarcinoma discovered incidentally have been demonstrated to do poorly with liver transplantation, typically dying of metastatic disease, leading most transplant centers to “steer clear” of suspected malignant biliary trees.
- Some authors have suggested that early transplantation (pre-emptive transplant) to decrease the risk of cholangiocarcinoma may be considered.
- One argument against this approach is that retransplantation rates appear to be higher with graft survival slightly shorter than other commonly transplanted disorders (i.e. PBC) and therefore PSC would not be an ideal setting to initiate early transplantation.
Liver transplantation
Despite limitations, the treatment of choice for end-stage PSC is liver transplantation.
- The reported 1- and 3-year survival rates are 85 and 75% respectively.
- Patients with PSC undergoing liver transplantation have significantly improved survival when compared to patients undergoing liver transplantation for most other indications.
- One of the challenges facing today’s hepatologists is not only the timing of the transplant, but determining when patients should be referred to transplant centers to optimize the results and minimize resource utilization.
- Although results with liver transplantation are improved, there is a shortage of donor livers for transplant and actual survival from the time of listing to transplant is much shorter than the results demonstrated after transplantation.
- In a recent Nordic study the 5- and 10-year survival from the time of listing for transplant was evaluated and demonstrated to be 68% and 58% respectively.
- Additionally, resource utilization is a clear concern and overall expenditures for PSC patients in liver transplantation have been demonstrated to be more favorable than those patients with alcoholic liver disease, which clearly is more common.
- Additionally, in the same study the cost per quality-adjusted life-year from time of listing for PBC was greater (29,000 pounds) than PSC (21,000 pounds).
Anther disease-specific complication that occurs in PSC transplantation is a recurrence of the underlying disease, which does occur pathologically in up to 30% of patients.
- Clearly, transplantation may be required for the usual complications of cirrhosis, such as recurrent variceal bleeding, diuretic-resistant ascites, and hepatic encephalopathy.
- Unlike other causes of cirrhosis, however, symptoms particular to PSC such as wasting, fatigue, pruritus, recurrent bacterial cholangitis, and jaundice without evidence of cholangiocarcinoma often prompt referral to transplant centers.
- In an era where organs such as livers are in short supply, it is often difficult to accommodate potential recipients (even if they are excellent candidates) and various strategies for transplant assessment are used.
- Rarely, other types of surgical procedures, such as hepaticojejunostomy or partial hepatectomy, can be considered.
- These types of procedures need to be performed with consultation of transplant orientated surgeons to ensure that they don’t preclude the patient from subsequent liver transplantation.
- In rare, selective cases long-term symptom relief may be obtained with selective surgical intervention.
- PSC patients seem to have a higher incidence of chronic ductopenic rejection post-liver transplant compared with PBC.
- In addition, colon cancer in patients with PSC and ulcerative colitis represents a significant cause of late mortality after liver transplantation; therefore, surveillance every 6 to 12 months by colonoscopy is recommended.
- Nonanastomotic biliary strictures, not associated with recurrent PSC, post-liver transplantation have been reported with increasing frequency and can be difficult to manage.
- Although definitive criteria for the diagnosis of PSC recurrence have not been established post-liver transplantation, some patients appear to develop a similar syndrome postoperatively.
- Males and an intact colon prior to transplant have been shown to have a higher risk of recurrent PSC in one pathological study of 152 transplanted PSC patients of whom 52 had recurrent PSC.
- Other conditions such as ischemia, cytomegalovirus infection, and chronic ductopenic rejection must also be considered in the differential diagnosis of post-transplant PSC.
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