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A. Characteristics navigator

  1. Chronic cholestatic liver disease, probably autoimmune
  2. Obliteration of intra- and extrahepatic bile ducts (alternating dilation and narrowing)
  3. Mainly affects young persons, average age 40 years, 65% male

B. Etiology [4] navigator

  1. Probably autoimmune: associated with HLA-B8, -DR3 and -DRw52a
  2. Strongly associated with autoimmune disorders including Inflammatory Bowel Disease (IBD)
  3. Inflammatory cells from the gut migrate to, and remain in, liver
    1. Infectious triggers in gut or liver may stimulate disease process
    2. No clear agent, but HIV, CMV, cryptosporidia, cryptococcus, trichosporon implicated
    3. Toxin: chemotherapy, bone marrow transplantation (usually called secondary SC)
  4. IBD Association
    1. SC is associated in with IBD in 75% of cases
    2. Of these, ~90% occur with ulcerative colitis (UC)
    3. Remainder have Crohn's Disease, usually Crohn's Colitis
    4. SC flares and progression independent of IBD flares
  5. SC can occur in patients with UC who have undergone colectomy

C. Associated Conditions (Table 3, Ref [2])navigator

  1. IBD: UC (90%), Crohn's Disease (10%)
  2. Immundodeficiency states
  3. Cryptosporidium infection
  4. Histiocytosis X (Langerhan's Cell Histiocytosis)
  5. Sickle Cell Anemia
  6. Auotimmune hemolytic anemia
  7. Hodgkin's Disease
  8. Cystic Fibrosis
  9. Celiac Sprue
  10. Chronic Pancreatitis
  11. Chronic Active Hepatitis
  12. Systemic Lupus Erythematosus
  13. Polymyositits

D. Symptoms and Signs [10] navigator

  1. Patients usually present with symptoms
  2. Jaundice - cholestatic
  3. Pruritus
  4. Fatigue
  5. Abdominal pain
  6. Hepato(spleno)megaly ~50%
  7. Cholangitis is inflammation of biliary tree
    1. Liver function test abnormalities, mainly alkaline phosphatase, 5' nucleotidase
    2. Abdominal pain
    3. Fever, rigors
  8. Steatorrhea - fat malabsorption (pancreas may be involved as well)

E. Laboratory Data and Diagnosisnavigator

  1. Diagnosis can only be confirmed by cholangiography (usually endoscopic)
  2. Marked increase in alkaline phosphatase, 5'-nucleotidase, GGT
  3. Modest increase in bilirubin and transaminases
  4. Autoantibodies
    1. Perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) in ~70%
    2. Anti-nuclear Antibodies (ANA) ~25%
    3. Anti-mitochondrial antibodies ~10%
  5. Specificity of P-ANCA [7]
    1. Overall staining ~70% of persons with SC (46 of 69 patients)
    2. Specific antigen reactions detected in 55% (37 of 69 patients)
    3. Bactericidal / permeability increasing protein in 46%
    4. Cathepsin G (a lysosomal enzyme) 23%
    5. Lactoferrin 22%
    6. Very few patients (3 of 69) had antibodies to proteinase III
  6. Fat Malabsorption
    1. Low serum levels of fat soluble vitamins
    2. Steatorrhea - quantitation by 72 hour fecal fat collection
  7. Endoscopy (ERCP or PTC) required for Diagnosis
    1. ERCP=endoscopic retrograde cholangiopancreatography
    2. PTC=Percutaneous Transhepatic Cholangiography
    3. Provides direct evaluation of biliary tree
    4. Band Strictures
    5. Diverticulum-like structures
    6. Classical appearance on ERCP
  8. Liver Biopsy
    1. Pericholangitis and periductal fibrosis
    2. Focal proliferation and obliteration of bile ducts
    3. Cholestasis
    4. Copper deposition

F. Medical Therapynavigator

  1. Disappointing overall results with single agents
  2. Pruritis
    1. Cholestyramine
    2. Ursodiol (Ursodeoxycholic acid, UDCA; Actigal®)
    3. Phenobarbital
    4. Ondansetron (Zofran®)
  3. Ursodiol (Actigal®) [9]
    1. May (transiently) improve liver function test results
    2. Usually improves pruritis
    3. No long term benefits in recent trials and no reduction in liver transplants [5]
    4. Trials should be conducted in very early disease where ursodiol may have a benefit
    5. In patients with ulcerative colitis and SC, ursodiol reduced risk of colonic dysplasia and neoplasia by 80% [11]
  4. Cyclosporine and Glucocorticoids
    1. Often used for control of associated inflammatory bowel disease
    2. Ineffective at controlling the progression of sclerosing cholangitis
  5. Methotrexate [6]
    1. Low doses may improve prognosis in patients without cirrhosis [4]
    2. Concern with methotrexate induced liver toxicity (usually hepatocyte disease)
  6. Combination Therapy [8]
    1. Azathioprine + prednisolone + ursodiol: 15 patients with primary sclerosing cholangitis
    2. Evalatuion for a median of 41 months (range 3-81 months)
    3. Azathioprine 1-1.5mg/kg/d + prednisolone 1mg/kg/d initially with taper
    4. Combined with Ursodiol 500-750mg po qd
    5. Combination therapy reduced liver enzymes in all patients
    6. Liver biopsy histology showed improvement in 6 of 10 evaluated patients
    7. Only one patient had progression of stenosis
    8. Overall fairly well tolerated (2 patients discontinued study for adverse reactions)
  7. Penicillamine for copper chelation
  8. Other Experimental Therapeutics
    1. Glucocorticoids
    2. Antibiotics

E. Complications of SCnavigator

  1. Bacterial Cholangitis - long term prophylaxis may be required
  2. Biliary Stones - ~30% of patients with SC
  3. Bile duct strictures
  4. Cholangiocarcinoma
  5. SC may be associated with ulcerative colitis

F. Liver Transplantation navigator

  1. For endstage liver disease:
    1. Variceal bleeding
    2. Recurrent cholangitis
    3. Encephalopathy
  2. Cyclosporine
  3. 50% 2 year survival

References navigator

  1. Martin M. 1993. Annu Rev Med. 44:221 abstract
  2. Ross AM IV, Anupindi SA, Balis UJ. 2003. NEJM. 348(15):1464 (Case Record) abstract
  3. Lee YM and Kaplan MM. 1995. NEJM. 332(14):924 abstract
  4. Grant AJ, Lalor PF, Salmi M, et al. 2002. Lancet. 359(9301):150 abstract
  5. Lindor KD. 1997. NEJM. 336(10):691 abstract
  6. Knox TA and Kaplan MM. 1994. Gastroenterol. 106:494 abstract
  7. Roozendaal C, de Wit AWMVM, Haagsma EB, et al. 1998. Am J Med. 105(5):393 abstract
  8. Schramm C, Schirmacher P, Helmreich-Becker I, et al. 1999. Ann Intern Med. 131(12):943 abstract
  9. Kowdley KV. 2000. Am J Med. 108(6):481 abstract
  10. Katz AJ and Graeme-Cook FM. 2000. NEJM. 342(25):1893 (Case Record)
  11. Tung BY, Emond MJ, Haggitt RC, et al. 2001. Ann Intern Med. 134(2):89 abstract