AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by cholestasis with inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. The condition may lead to cirrhosis of the liver with portal hypertension. PSC has been reported more frequently since the development of endoscopic retrograde cholangiopancreatography (ERCP); until 1970, fewer than 100 patients with PSC had been reported. It is the fourth leading indication for liver transplantation in adults.

Pathophysiology

The etiology of this disease remains unknown, but a variety of factors are thought to be involved. An autoimmune mechanism is suggested, since approximately 75-90% of patients with PSC have inflammatory bowel disease (IBD). However, only approximately 4% of patients with IBD have or develop PSC. A marked increase in serum autoantibody levels occurs in patients with PSC as well, with antineutrophil cytoplasmic antibodies (ANCA) in 87%, anticardiolipin (aCL) antibodies in 66%, and antinuclear antibodies (ANA) in 53%.

In biliary ducts, an inflammatory response to chronic or recurrent bacterial infection in the portal circulation and from exposure to toxic bile acids has been postulated. A genetic predisposition has been suggested, because these patients have an increased prevalence of HLA-B8, HLA-DR3, and HLA-Drw52a. Ischemic damage to the biliary tree has also been postulated, since surgical trauma to the biliary tract can cause similar damage and because of the high number of patients with PSC who are ANCA–positive as observed in other vasculitides. Therefore, the most plausible concept of the pathogenesis of PSC involves the exposure of genetically predisposed individuals to an environmental antigen that subsequently elicits an aberrant immune response, leading to development of the disease.

Frequency

United States

In the United States, the prevalence rate of PSC as such is not known. Inferences are drawn based on the strong relationship with IBD. Prevalence is estimated at 6.3 cases per 100,000 population.

International

Western Europe is thought to have approximately the same prevalence rate as the United States, though Scandinavian countries report a somewhat higher rate. In many developing countries with limited access to advanced health care, the prevalence of PSC is probably underestimated, since the diagnosis cannot be confirmed without ERCP. The association of PSC with IBD may vary; for instance, in Japan, only 23% of patients with PSC have IBD (Okada, 1996).

Mortality/Morbidity

PSC is generally a progressive disease that eventually culminates in portal hypertension and cirrhosis with complications. The median length of survival from diagnosis to death is approximately 12 years. Liver transplantation is the only treatment modality that appears to change the prognosis.

Race

A survey of the literature does not reveal a racial bias for PSC, but studies on this aspect of the disease are rather limited. Based on the epidemiological data available for IBD, the Jewish population might be expected to have a 2- to 4-fold higher prevalence, followed by (in descending order of frequency) whites, African Americans, Hispanics, and Asians.

Sex

Approximately 70% of patients with PSC are men with a mean age of diagnosis around 40 years. Patients with PSC but without IBD are more likely to be women and to be older at diagnosis.

Age

The mean age of diagnosis is 39 years. Diagnosis is usually made in symptomatic patients. A person may have the disease but be asymptomatic.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Approximately 75-90% of patients have IBD. Of these, 87% have ulcerative colitis and 13% have Crohn colitis; however, the course of IBD is not related to PSC. Most patients are male and are diagnosed at a mean age of approximately 40 years.

Symptoms upon initial presentation consist of fatigue, jaundice, pruritus, and right upper quadrant pain. The clinical course varies a great deal. Symptoms may remit and then recur spontaneously. Occasionally, patients with PSC may have an acute hepatitis-like presentation. Recurrent febrile episodes of bacterial cholangitis occur in 10-15% of patients during the course of PSC. Pancreatic duct involvement in PSC is uncommon, and pancreatic exocrine insufficiency is not correlated when ductal abnormalities are noted.

Patients with asymptomatic PSC comprise 20-40% of the cohort in some large studies. This high percentage is thought to be attributable to the practices of screening patients with ulcerative colitis for elevated alkaline phosphatase levels and performing ERCP in them. Cirrhosis, portal hypertension, and liver failure occur in progressive disease, with symptoms consistent with these entities, including variceal bleeding, ascites, and hepatic encephalopathy. The risk for cholangiocarcinoma is increased significantly in patients with PSC.

The median length of survival from diagnosis to death or liver transplantation is 10-15 years. Patients who were symptomatic at diagnosis have a shorter survival time compared to those who were asymptomatic.

Physical

Physical examination results are significant for jaundice, weight loss, and, occasionally, pruritic skin marks. Hepatomegaly is common, and splenomegaly is present in up to one third of patients with PSC. As the disease progresses, signs of liver failure, including spider angiomata, ascites, and muscle atrophy, become apparent.

Causes

As previously noted, the exact cause of PSC remains unknown. The etiology is thought to be multifactorial, including genetic predisposition, exposure to an environmental antigen, and subsequent aberrant immunological response to that stimulus.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Other entities in the differential diagnoses include congenital diseases (eg, Caroli disease, choledochal cysts) and secondary cholangiopathy as observed in patients with collagen vascular diseases (eg, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis) and in those with infiltrative diseases (eg, mediastinal fibrosis, Riedel thyroiditis, eosinophilic cholangitis, histiocytosis X). Infectious causes from parasitic, fungal, viral, or bacterial infections, or from recurrent cholangitis itself, especially in patients who are immunocompromised, can cause multifocal liver abscesses that lead to a PSC-like appearance of the bile duct.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Liver function tests: These tests are the most valuable in the laboratory workup.
• • Serum alkaline phosphatase dominates the profile, which is cholestatic in nature. Alkaline phosphatase levels are usually 3-5 times reference range values. Alkaline phosphatase can be divided into its various fractions to ascertain its origin from liver disease as opposed to bone disease. Serum gamma-glutamyl transpeptidase levels mirror this rise and can help differentiate cholestasis from bone disease. Some patients with hypothyroidism, hypophosphatemia, or zinc or magnesium deficiency may have normal alkaline phosphatase levels.
  • Serum aminotransferase levels are increased but not markedly so. Serum bilirubin levels, with the conjugated component, are usually increased, but fluctuations in the level can occur. Serum albumin levels decrease later in the course of the disease, and the presence of hypoalbuminemia earlier in the disease may indicate active IBD.
  • Hypergammaglobulinemia is present in 30% of patients, and 50% have increased immunoglobulin (IgM) levels. p-ANCA, aCL antibodies, and ANA are present in up to 84%, 66%, and 53% of patients, respectively.

Imaging Studies

• ERCP is considered the criterion standard for confirming a diagnosis of PSC. Radiological features in ERCP include multiple strictures and dilations of the intrahepatic and extrahepatic biliary ducts.
• Transhepatic cholangiography is performed when ERCP is unsuccessful.
• Because it is noninvasive, magnetic resonance cholangiopancreatography (MRCP) is rapidly developing as the preferred study to evaluate the bile ducts. As image quality continues to improve, MRCP may become the criterion standard.

Procedures

• Liver biopsy is rarely diagnostic of PSC, although it does help determine both the stage and the prognosis of the disease.

Histologic Findings

A variety of histopathologic liver changes are noted in patients with PSC. The most common characteristic feature is onionskin fibrosis, which describes the appearance of periductal concentric fibrosis around the interlobular and septal bile ducts. This is present in only half of all biopsy specimens from patients with otherwise typical PSC, whereas concentric fibrosis with obliteration of the small ducts (obliterative fibrous cholangitis)—a virtually diagnostic histopathologic lesion—is found in fewer than 10% of biopsy specimens.

Periductal fibrosis may be accompanied by infiltrates of inflammatory cells. Piecemeal necrosis, as occurs in patients with chronic hepatitis, may be observed as well.

Staging

In 1981, Ludwig and associates described 4 stages of PSC, as follows:

• Stage 1 - Portal hepatitis, degeneration of bile ducts with inflammatory cell infiltrate
• Stage 2 - Extension of disease to periportal area with prominent bile ductopenia
• Stage 3 - Septal fibrosis and necrosis
• Stage 4 - Frank cirrhosis

The most characteristic histological feature of onionskin fibrosis, which consists of concentric fibrosis around the septal bile ducts, is noted in only approximately 10% of biopsy specimens.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

PSC is a chronic progressive disease with no curative medical therapy. The goals of medical management are to treat the symptoms and to prevent or treat the known complications. Liver transplantation is the only effective therapy and is indicated in end-stage liver disease.

Surgical Care

Surgical therapy includes liver transplantation, proctocolectomy (for patients with ulcerative colitis), and biliary reconstructive procedures. Note that proctocolectomy in patients with both PSC and ulcerative colitis has no effect on the course of PSC.

Indications for liver transplantation include variceal bleed or portal gastropathy, intractable ascites, recurrent cholangitis, progressive muscle wasting, and hepatic encephalopathy. Centers are reporting survival rates of 93.7%, 92.2%, 86.4%, and 69.8% at 1, 2, 5, and 10 years, respectively. However, PSC recurs in 15-20% of patients after transplantation.

Consultations

A gastroenterologist must be consulted. When needed, surgical consultation should be initiated by the gastroenterologist and when liver transplantation is offered. An endocrinologist may be consulted for management of bone disease. Endoscopic dilation of dominant strictures, with or without stenting, has been shown to alleviate cholestasis and to improve laboratory test results; however, it is not currently believed to affect disease progression. Ruling out malignancy in these strictures is difficult.

Diet

Patients with steatorrhea are encouraged to include medium-chain triglycerides in their diet. Fat-soluble vitamin deficiency correction should be attempted by supplementation. Oral supplementation is necessary if associated pancreatic enzyme deficiency is present. Calcium supplementation for bone disease may also be needed.

Activity

Physical activity should not be restricted; however, in patients with osteoporosis, the possibility of fractures should temper the type of activity allowed.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No medical therapy has been proven effective for PSC. Therapy is aimed at treating symptoms and managing complications. Liver transplantation is the only therapy that can alter the eventual outcome. Immunosuppressants, chelators, and steroids are used in an attempt to control the disease process but have not shown significant benefit.

Ursodeoxycholic acid improves the liver function profile in some patients and, in conjunction with endoscopic dilation, has shown a survival benefit in some studies. Trials using ursodeoxycholic acid in higher doses and earlier in the disease course are ongoing.

Drug Category: Immunosuppressant agents

With the possibility of an autoimmune pathogenesis for PSC, immunosuppressive therapy has been used in treatment of PSC. Results of therapeutic trials, however, have been disappointing.

Drug Name	Cyclosporine (Sandimmune, Neoral)
Description	Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft vs host disease for a variety of organs. For both children and adults, base dosing on ideal body weight.
Adult Dose	Initial dose: 14-18 mg/kg PO 4-12 h before organ transplantation Alternative initial dose: 5-6 mg/kg IV 4-12 h before organ transplantation Maintenance dose: 5-15 mg/kg PO qd or divided bid Alternative maintenance dose: 2-10 mg/kg/d IV divided q8-12h
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; uncontrolled hypertension or malignancies; concomitant administration with PUVA or UV-B radiation in psoriasis owing to possible increased risk of cancer
Interactions	Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin; methylprednisolone and cyclosporine mutually inhibit one another, resulting in increased plasma levels of each drug
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Frequently evaluate renal and liver functions by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use for persons who cannot take PO

Drug Name	Prednisone (Orasone, Deltasone, Meticorten, Sterapred)
Description	Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.
Adult Dose	5-60 mg PO qd or divided bid/qid; taper over 2 wk as symptoms resolve
Pediatric Dose	4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve
Contraindications	Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective-tissue infections; fungal or tubercular skin infections; GI bleeding or ulceration
Interactions	Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Name	Methotrexate (Folex PFS, Rheumatrex)
Description	Antimetabolite used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. Inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be used as carriers of single-carbon groups in the synthesis of purine nucleotides and thymidylate. Methotrexate therefore interferes with DNA synthesis, repair, and cellular replication.
Adult Dose	7.5 mg PO qwk; alternatively, 2.5 mg PO q12h for 3 doses given qwk; in either schedule, dosages may be gradually adjusted to achieve optimal response; typically, not to exceed 20 mg total weekly dose
Pediatric Dose	Recommended starting dose is 10 mg/m2 administered qwk, although doses up to 30 mg/m2/wk have reportedly been used in children, too few published data are available to allow assessment of how doses >20 mg/m2/wk might affect risk of serious toxicity in children
Contraindications	Documented hypersensitivity; pregnancy and breastfeeding mothers; alcoholism, alcoholic liver disease, or other chronic liver disease; laboratory evidence of immunodeficiency syndromes, psoriasis, or rheumatoid arthritis; preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia
Interactions	Oral aminoglycosides may decrease absorption and blood levels; charcoal lowers levels; coadministration with etretinate may increase hepatotoxicity; folic acid or its derivatives contained in some vitamins may decrease response; probenecid, NSAIDs, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase plasma levels; may decrease phenytoin plasma levels; may increase plasma levels of thiopurines
Pregnancy	X - Contraindicated in pregnancy
Precautions	Monitor CBC counts monthly and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg, dehydration); has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood cell counts occurs; fatal reactions reported when administered concurrently with NSAIDs

Drug Category: Chelating agents

Observation of increased serum, urinary, and hepatic copper concentrations in patients with PSC has prompted the use of penicillamine, which is a chelator.

Drug Category: Gallstone dissolution agents

Thought to remove toxic bile acids from the enterohepatic circulation and to offer protection to the bile duct from injury.

Drug Category: Antilipemic agents

Are thought to decrease pruritus by combining with bile acids in the intestine and by causing them to be excreted because of nonreabsorption.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Further inpatient care is dictated by the admitting diagnosis and complications and may involve any or all of the previously discussed treatment options.

Further Outpatient Care

• Further outpatient care is dictated by the stage and degree of progression of the disease. It involves care by a gastroenterologist, who must monitor the patient's condition with frequent laboratory tests and maintain vigilance for the many complications of PSC. Suitability for liver transplantation should be determined expeditiously and, if appropriate, offered to the patient.

Deterrence/Prevention

• PSC is a progressive disease, and no preventive strategies have been proven effective. Stopping smoking and/or drinking may decrease or delay the chances of developing cholangiocarcinoma.

Complications

• Chronic cholestasis leads to steatorrhea, fat-soluble vitamin (A, D, E, and K) deficiency, metabolic bone disease with osteoporosis, and calorie loss with resultant weight loss.
• Cholangitis and cholelithiasis occur more frequently in patients with PSC.
• Cholangiocarcinoma reportedly occurs in association with PSC in 6-30% of patients and in up to 30-40% of patients with PSC on autopsy. The development of cholangiocarcinoma remains unpredictable in any given patient, and no reliable serological tumor markers have been identified.
• Secondary biliary cirrhosis due to chronic cholestasis occurs in patients with PSC. Portal hypertension with variceal bleeding, ascites, and liver failure then ensue.
• Dominant biliary strictures can be identified in about 20% of patients with PSC and must be differentiated from cholangiocarcinoma. Strictures cause cholestasis with jaundice and pruritus and may also result in cholangitis.
• The risk of colon cancer is increased for patients with both ulcerative colitis and PSC versus those with only ulcerative colitis.

Prognosis

• PSC is a progressive disorder that ultimately leads to hepatic failure. Median survival time without liver transplantation is about 12 years. Survival prospects are more dismal for those who are symptomatic at diagnosis. The following variables influence prognosis:
• • Revised Mayo Clinic model
  • • Age
    • Serum bilirubin, albumin, and aspartate aminotransferase levels
    • Variceal bleeding history
  • Child-Turcotte-Pugh scale
  • • Grade of encephalopathy
    • Presence or absence of ascites
    • Serum albumin level
    • Prothrombin time
    • Bilirubin level

Patient Education

• Educate patients regarding the natural course of the disease, expected complications, and treatment strategies, including liver transplantation.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to conscientiously monitor and treat complications, including those caused by nutritional deficits (eg, night blindness, osteoporosis with resultant fractures)
• Failure to recognize that worsening jaundice, pruritus, or weight loss may indicate development of a stricture or cholangiocarcinoma
• Failure to perform colonoscopy or flexible sigmoidoscopy in patients with PSC without a history of IBD
• Failure to conduct periodic colonoscopic surveillance of patients with PSC and ulcerative colitis to exclude colonic neoplasia
• Failure to monitor for toxicity in patients taking certain immunosuppressant drugs

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Taylor BV, Wijdicks EF, Poterucha JJ, Weisner RH. Chronic inflammatory demyelinating polyneuropathy complicating liver transplantation. Ann Neurol. Nov 1995;38(5):828-31. [Medline].
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Article Last Updated: Feb 14, 2007