A. Characteristics

1. Usually affects middle aged women (~90%)
   1. Incidence is ~8 per million population per year
   2. Prevalence is about 10 fold higher than incidence (about 20,000 persons in USA)
2. Chronic, progressive destruction of septal and interlobular bile ducts
   1. Most patients with specific autoantibodies progress over 10 years with symptoms
   2. Symptomatic patients progress over 2-10 years with increasing liver destruction
   3. Some therapies appear to slow progression
   4. However, most patients progress to liver failure with need for transplantation
3. Anti-Mitochondrial Antibodies (AMA)
   1. AMA positive in >95% cases of PBC
   2. The most common target antigen is pyruvate dehydrogenase complex
   3. Found on the inner membrane of mitochrondria
   4. Anti-branched chain ketoacid (such as oxoglutarate) dehydrogenase Abs also occur
4. Other Autoantibodies
   1. About 50% of patients have antinuclear antibodies (ANA+)
   2. Thyroid disease may occur in up to 20% of PBC, usually Hashimoto Type
5. These and other data strongly suggest autoimmune etiology

B. Symptoms and Signs

1. Fatigue
   1. Presenting symptom in ~20% of cases
   2. Occurs in ~75% of cases
2. Pruritus is usually first specific symptom
   1. Occurs at presentation in nearly 20% of cases
   2. Elevated total bilirubin often without jaundice
   3. Often responds well to ursodeoxycholic acid
   4. Patients with pruritus and AMA likely have PBC [2]
3. Malabsorption - particularly fats and fat soluble vitamins
4. Jaundice - sign of end stage disease in most cases [3]
5. Endstage
   1. Coagulopathy - very late stage disease, prolonged PT
   2. Esophageal Varices
   3. Encephalopathy
   4. Hepatorenal Syndrome

C. Pathogenesis and Evaluation [3]

1. Blood Test Abnormalities
   1. Alkaline phosphatase and 5'-nucleotidase elevations
   2. Unusual for transaminases to be >2-3 fold elevated
   3. Bilirubin is elevated only in later stages of disease
   4. Albumin drops and prothrombin time is prolonged in late stage disease
   5. Elevated levels of total immunoglobulin often found (even in early disease)
   6. Hypercholesterolemia found in ~50% of patients (often with very high HDL)
2. Autoantibodies
   1. >90% of patients have AMA
   2. AMA usually specifically against pyruvate dehydrogenase complex
   3. AMA often detectable years before clinical signs
   4. Majority of patients are also usually positive for antinuclear antibodies
   5. Patients positive for AMA and LFT abnormalities nearly all have PBC [2]
   6. Thyroid autoantibodies are also often found
   7. Unclear if autoantibodies are pathogenic since their targets are found everywhere
3. Hepatic Histology
   1. Liver biopsy is generally used to confirm diagnosis
   2. Bile duct inflammation is characteristic of the disease
   3. CD8+ T lymphocytes appear to be responsible for bile duct destruction
   4. Majority of lymphocytes in portal triads are CD4+ helper T cells
   5. Granuloma formation is common with macrophages (histiocytes) and lymphocytes
   6. Granulomas are typically noncaseating
   7. Residual scarring is left as disease progresses
4. Ultrasonography and CT scanning is not generally required
5. HIstologic Staging
   1. Stage I: inflammation in portal space
   2. Stage II: Inflammation extending into hepatic parenchyma
   3. Stage III: Septal or bridging fibrosis
   4. Stage IV: Cirrhosis with regenerative nodules

D. Extrahepatic Disorders Associated with PBC

1. Sjogren Syndrome
   1. As keratoconjunctivitis sicca
   2. 85% of patients
2. Renal Tubular Acidosis (50%)
3. Gallstones (30%)
4. Arthropathy or Inflammatory Arthritis
5. Hypothyroidism - autoimmune, 15%
6. Scleroderma (15%) and CREST Syndrome (5%)
7. Reduced Bone Density
   1. Osteopenia ~35%
   2. Osteoporosis ~10%
8. Hyperlipidemia [2]
   1. However, no increased risk of atherosclerosis in PBC
   2. Cholesterol and triglycerides increased
   3. Levels improved with UDCA (see below)
   4. Statins and ezetimibe appear to be safe in PBC

E. Therapy

1. Bathing: long baths often reduces pruritus
2. Treatment of Jaundice and/or Pruritus
   1. Cholestyramine (Questran®): ionic bile salt absorption, also lowers cholesterol
   2. Phenobarbital: stimulates bile flow
   3. UV light: pyrinogens are converted to less active forms
   4. Naloxone (Narcan®): subcutaneous or intravenous provides relief in many patients [4]
   5. Urosdeoxholic acid (UDCA, ursodiol, Actigall®) - see below
3. Colchicine
   1. Reduces serum liver function levels, but less effective than UDCA
   2. Reduced intensity of pruritus in most studies
   3. May delay need for liver transplantation
   4. 0.6mg po bid is used
   5. May synergize with UDCA
4. Methotrexate
   1. Third line for patients with incomplete response to UDCA and colchicine
   2. Dose is 0.25mg/kg/week
   3. Lowers serum levels of liver enzymes, cholesterol and IgM
   4. May improve liver histology
5. Investigational Drugs [1,2]
   1. Mycophenolate mofetil (Celcept®) is under investigation
   2. Cyclosporine, azathioprine, glucocorticoids not effective
6. Liver Transplantation
   1. Only definitive therapy for PBC with liver failure
   2. ~20% of patients require transplantation within 2 years of diagnosis
   3. UDCA therapy does not appear to reduce need for transplantation in PBC patients [7]
   4. Living related donor for transplant should be considered [6]
   5. Five year survival 85%
7. Metabolic Bone Disease
   1. Reduced bone formation and elevated osteoporosis risk associated with PBC
   2. Oral calcium 1000-1200mg/d and weight bearing activity recommended
   3. Vitamin D deficiency can occur due to fat-soluble vitamin malabsorption
   4. Oral vitamin D replacement should be initiated if serum values are low
   5. Strongly consider bisphosphonates
8. Other Vitamin Deficiency
   1. Vitamin A deficiency (20% of patients) - replacement with 25-50,000 IU 2-3X / week
   2. Vitamin D deficiency - 400 IU daily replacement
   3. Vitamin K deficiency - 5-10mg daily replacement

E. UDCA (Actigall®) [1,2,5,6]

1. Bile acid with reduced hepatotoxicity compared with endogenous bile acids [5,6]
   1. Displaces potentially hepatotoxic bile acids from bile and serum
   2. Competes with endogenous bile acids for absorption in terminal ileum
   3. Diminishes toxicity and cholestasis of other bile acids
   4. Stabilizes hepatocyte membranes and allows restoration of normal cell junctions
   5. Immunomodulation - redcuces aberrant HLA type 1 expression on hepatocytes
   6. Induces reduction in cytokine levels
   7. Overall blocks apoptosis and mitochondrial dysfunction of hepatocytes
   8. With chronic UDCA therapy over time, accounts for 40-50% of total bile-acid pool
2. Indications [5]
   1. Patients with any stage of PBC will show benefit from UDCA
   2. Probably best in patients with earlier (reversible) disease
   3. May be initiated without liver biopsy
3. Efficacy [7]
   1. Effective in improving lab parameters of liver injury (AST, ALT, Alk Phos, bilirubin)
   2. Unclear if it reduces pruritus and other symptoms of PBC
   3. UDCA does not appear to reduce need for liver transplant or mortality in PBC [7]
   4. Reduces risk of developing new esophageal varices (placebo rate 58%, ursodiol 16%) [8]
4. Well tolerated; diarrhea, nausea may occur in some patients
5. Dosing [5]
   1. Oral 13-15mg/kg/d divided into three doses oras a single daily dose
   2. Lower or higher doses are not as effective or have increased side effects
6. If cholestyramine is used, at least 4 hours should elapse between it and UDCA
7. Monitor liver function at 3 month intervals after initiation of therapy

References

1. Talwalkar JA and Lindor KD. 2003. Lancet. 362(9377):53
2. Kaplan MM and Gershwin ME. 2005. NEJM. 353(12):1261
3. Trauner M, Meier PJ, Boyer JL. 1998. NEJM. 339(17):1217
4. Bergasa NV, Alling DW, Talbot TL, et al. 1995. Ann Intern Med. 123(3):161
5. Lindor K. 2007. NEJM. 357(15):1524
6. Kowdley KV. 2000. Am J Med. 108(6):481
7. Gong Y, Huang Z, Christensen E, Gluud C. 2007. Am J Gastroenterol. 102(8):1799
8. Lindor KD, Jorgensen RA, Therneau TM, et al. 1997. Mayo Clin Proc. 72(12):1137