Chapter 100
Primary Biliary Cirrhosis
Marlyn J. Mayo,
Dwain L. Thiele,
Marlyn J. Mayo
University of Texas Southwestern Medical Center, Dallas, TX, USA
Search for more papers by this authorDwain L. Thiele
University of Texas Southwestern Medical Center, Dallas, TX, USA
Search for more papers by this authorMarlyn J. Mayo,
Dwain L. Thiele,
Marlyn J. Mayo
University of Texas Southwestern Medical Center, Dallas, TX, USA
Search for more papers by this authorDwain L. Thiele
University of Texas Southwestern Medical Center, Dallas, TX, USA
Search for more papers by this authorBook Editor(s):Daniel K. Podolsky MD,
Michael Camilleri MD,
J. Gregory Fitz MD FAASLD,
Anthony N. Kalloo MD,
Fergus Shanahan MD,
Timothy C. Wang MD,
Daniel K. Podolsky MD
President, University of Texas Southwestern Medical Center, Professor of Internal Medicine, Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA
Search for more papers by this authorMichael Camilleri MD
Executive Dean for Development, Atherton and Winifred W. Bean Professor, Professor of Medicine, Physiology and Pharmacology, Distinguished Investigator, Mayo Clinic, Rochester, MN, USA
Search for more papers by this authorJ. Gregory Fitz MD FAASLD
Executive Vice President for Academic Aff airs and Provost, University of Texas Southwestern Medical Center, Dean, Professor of Internal Medicine, Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA
Search for more papers by this authorAnthony N. Kalloo MD
Professor of Medicine, Johns Hopkins University School of Medicine, Director, Division of Gastroenterology & Hepatology, Johns Hopkins Hospital, Baltimore, MD, USA
Search for more papers by this authorFergus Shanahan MD
Professor and Chair, Department of Medicine, Director, Alimentary Pharmabiotic Centre, University College Cork, National University of Ireland, Cork, Ireland
Search for more papers by this authorTimothy C. Wang MD
Chief, Division of Digestive and Liver Diseases, Silberberg Professor of Medicine, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY, USA
Search for more papers by this authorFirst published: 27 November 2015
Summary
Primary biliary cirrhosis (PBC) is considered an autoimmune disease. Clinically, PBC shares features with other autoimmune diseases such as predominance in middle-aged females and frequent coincidence with other autoimmune disorders. The diagnosis of PBC is suspected when a patient presents with evidence of chronic cholestasis. The differential diagnosis of a patient who presents with chronic cholestatic liver tests may initially include extrahepatic obstruction, or intrahepatic cholestatic liver diseases, as well as granulomatous and infiltrative diseases of the liver. Clinical progression is foretold by worsening of specific biochemical parameters, particularly serum bilirubin levels. Pruritus is a common and often a vexing symptom of patients with PBC. Therapy with ursodeoxycholic acid (UDCA) at a dose of 13-15 mg/kg/day has become the mainstay of therapy for PBC. Managing the complications of cholestasis comprises a considerable portion of the clinician's treatment of the patient with PBC.
References
- Chazouilleres O., Wendum D., Serfaty L., et al. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology 1998; 28: 296.
- Gershwin M.E., Mackay I.R., Sturgess A., et al. Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol 1987; 138: 3525.
- Gershwin M.E., Selmi C., Worman H.J., et al. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology 2005; 42: 1194.
- Lindor K.D., Gershwin M.E., Poupon R., et al. Primary biliary cirrhosis. Hepatology 2009; 50: 291.
- Ludwig J., Dickson E.R., McDonald G.S. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol 1978; 379: 103.
- Poupon R.E., Lindor K.D., Cauch-Dudek K., et al. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997; 113: 884.
- Prince M.I., Chetwynd A., Craig W.L., et al. Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut 2004; 53: 865.
- Prince M., Chetwynd A., Newman W., et al. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology 2002; 123: 1044.
- Selmi C., Mayo M.J., Bach N., et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 2004; 127: 485.
- Poupon R, Chazouilleres O, Balkau B, et al. Clinical and biochemical expression of the histopathological lesions of primary biliary cirrhosis. UDCA-PBC Group. J Hepatol 1999; 30: 408.
- Culp KS, Fleming CR, Duffy J, et al. Autoimmune associations in primary biliary cirrhosis. Mayo Clin Proc 1982; 57: 365.
- Gershwin ME, Mackay IR, Sturgess A, et al. Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol 1987; 138: 3525.
- Gershwin ME, Rowley M, Davis PA, et al. Molecular biology of the 2-oxo-acid dehydrogenase complexes and anti-mitochondrial antibodies. Prog Liver Dis 1992; 10: 47.
- Krams SM, Surh CD, Coppel RL, et al. Immunization of experimental animals with dihydrolipoamide acetyltransferase, as a purified recombinant polypeptide, generates mitochondrial antibodies but not primary biliary cirrhosis. Hepatology 1989; 9: 411.
- Leung PS, Yang GX, Dhirapong A, et al. Animal models of primary biliary cirrhosis: materials and methods. Methods Mol Biol 2012; 900: 291.
- Joplin R, Lindsay JG, Hubscher SG, et al. Distribution of dihydrolipoamide acetyltransferase (E2) in the liver and portal lymph nodes of patients with primary biliary cirrhosis: an immunohistochemical study. Hepatology 1991; 14: 442.
- Odin JA, Huebert RC, Casciola-Rosen L, et al. Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J Clin Invest 2001; 108: 223.
- Selmi C, Balkwill DL, Invernizzi P, et al. Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology 2003; 38: 1250.
- Stemerowicz R, Hopf U, Moller B, et al. Are antimitochondrial antibodies in primary biliary cirrhosis induced by R(rough)-mutants of enterobacteriaceae? Lancet 1988; 2: 1166.
- Hopf U, Moller B, Stemerowicz R, et al. Relation between Escherichia coli R(rough)-forms in gut, lipid A in liver, and primary biliary cirrhosis. Lancet 1989; 2: 1419.
- Butler P, Valle F, Hamilton-Miller JM, et al. M2 mitochondrial antibodies and urinary rough mutant bacteria in patients with primary biliary cirrhosis and in patients with recurrent bacteriuria. J Hepatol 1993; 17: 408.
- Long SA, Quan C, Van de Water J, et al. Immunoreactivity of organic mimeotopes of the E2 component of pyruvate dehydrogenase: connecting xenobiotics with primary biliary cirrhosis. J Immunol 2001; 167: 2956.
- Leung PS, Quan C, Park O, et al. Immunization with a xenobiotic 6-bromohexanoate bovine serum albumin conjugate induces antimitochondrial antibodies. J Immunol 2003; 170: 5326.
- Ohba K, Omagari K, Kinoshita H, et al. Primary biliary cirrhosis among atomic bomb survivors in Nagasaki, Japan. J Clin Epidemiol 2001; 54: 845.
- Gershwin ME, Selmi C, Worman HJ, et al. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology 2005; 42: 1194.
- Prince MI, Ducker SJ, James OF. Case-control studies of risk factors for primary biliary cirrhosis in two United Kingdom populations. Gut 2010; 59: 508.
- Zein CO, Beatty K, Post AB, et al. Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: a cross validated retrospective assessment. Hepatology 2006; 44: 1564.
- Prince MI, Chetwynd A, Diggle P, et al. The geographical distribution of primary biliary cirrhosis in a well-defined cohort. Hepatology 2001; 34: 1083.
- Watson RG, Angus PW, Dewar M, et al. Low prevalence of primary biliary cirrhosis in Victoria, Australia. Melbourne Liver Group. Gut 1995; 36: 927.
- Witt-Sullivan H, Heathcote J, Cauch K, et al. The demography of primary biliary cirrhosis in Ontario, Canada. Hepatology 1990; 12: 98.
- Parikh-Patel A, Gold E, Mackay IR, et al. The geoepidemiology of primary biliary cirrhosis: contrasts and comparisons with the spectrum of autoimmune diseases. Clin Immunol 1999; 91: 206.
- Howel D, Fischbacher CM, Bhopal RS, et al. An exploratory population-based case-control study of primary biliary cirrhosis. Hepatology 2000; 31: 1055.
- Selmi C, Mayo MJ, Bach N, et al. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 2004; 127: 485.
- Feizi T, Naccarato R, Sherlock S, et al. Mitochondrial and other tissue antibodies in relatives of patients with primary biliary cirrhosis. Clin Exp Immunol 1972; 10: 609.
- Neuberger J. Liver transplantation for primary biliary cirrhosis: indications and risk of recurrence. J Hepatol 2003; 39: 142.
- Liu X, Invernizzi P, Lu Y, et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet 2010; 42: 658.
- Jackson H, Solaymani-Dodaran M, Card TR, et al. Influence of ursodeoxycholic acid on the mortality and malignancy associated with primary biliary cirrhosis: a population-based cohort study. Hepatology 2007; 46: 1131.
- Krams SM, Van de Water J, Coppel RL, et al. Analysis of hepatic T lymphocyte and immunoglobulin deposits in patients with primary biliary cirrhosis. Hepatology 1990; 12: 306.
- Hirschfield GM, Liu X, Xu C, et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 2009; 360: 2544.
- Kong F, Li JX, Li P, et al. Association of TNFSF4 polymorphisms with susceptibility to primary Sjogren's syndrome and primary biliary cirrhosis in a Chinese Han population. Clin Exp Rheumatol 2013; 31: 546.
- Marucci L, Ugili L, Macarri G, et al. Primary biliary cirrhosis: modalities of injury and death in biliary epithelium. Dig Liver Dis 2001; 33: 576.
- Sherlock S, Scheuer PJ. The presentation and diagnosis of 100 patients with primary biliary cirrhosis. N Engl J Med 1973; 289: 674.
- James O, Macklon AF, Watson AJ. Primary biliary cirrhosis–a revised clinical spectrum. Lancet 1981; 1: 1278.
- Prince MI, Chetwynd A, Craig WL, et al. Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut 2004; 53: 865.
- Crowe J, Christensen E, Doniach D, et al. Early features of primary biliary cirrhosis: an analysis of 85 patients. Am J Gastroenterol 1985; 80: 466.
- Heathcote J. The clinical expression of primary biliary cirrhosis. Semin Liver Dis 1997; 17: 23.
- Heathcote EJ. Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines. Hepatology 2000; 31: 1005.
- Newton JL, Hudson M, Tachtatzis P, et al. Population prevalence and symptom associations of autonomic dysfunction in primary biliary cirrhosis. Hepatology 2007; 45: 1496.
- Jones EA, Bergasa NV. The pathogenesis and treatment of pruritus and fatigue in patients with PBC. Eur J Gastroenterol Hepatol 1999; 11: 623.
- Bergasa NV, Thomas DA, Vergalla J, et al. Plasma from patients with the pruritus of cholestasis induces opioid receptor-mediated scratching in monkeys. Life Sci 1993; 53: 1253.
- Laurin JM, DeSotel CK, Jorgensen RA, et al. The natural history of abdominal pain associated with primary biliary cirrhosis. Am J Gastroenterol 1994; 89: 1840.
- Del Puppo M, Kienle MG, Petroni ML, et al. Serum 27-hydroxycholesterol in patients with primary biliary cirrhosis suggests alteration of cholesterol catabolism to bile acids via the acidic pathway. J Lipid Res 1998; 39: 2477.
- Epstein O, Arborgh B, Sagiv M, et al. Is copper hepatotoxic in primary biliary cirrhosis? J Clin Pathol 1981; 34: 1071.
- Zurgil N, Bakimer R, Kaplan M, et al. Anti-pyruvate dehydrogenase autoantibodies in primary biliary cirrhosis. J Clin Immunol 1991; 11: 239.
- Dahnrich C, Pares A, Caballeria L, et al. New ELISA for detecting primary biliary cirrhosis-specific antimitochondrial antibodies. Clin Chem 2009; 55: 978.
- Szostecki C, Guldner HH, Will H. Autoantibodies against “nuclear dots” in primary biliary cirrhosis. Semin Liver Dis 1997; 17: 71.
- Wichmann I, Montes-Cano MA, Respaldiza N, et al. Clinical significance of anti-multiple nuclear dots/Sp100 autoantibodies. Scand J Gastroenterol 2003; 38: 996.
- Bogdanos DP, Vergani D, Muratori P, et al. Specificity of anti-sp100 antibody for primary biliary cirrhosis. Scand J Gastroenterol 2004; 39: 405; author reply 7.
- Zuchner D, Sternsdorf T, Szostecki C, et al. Prevalence, kinetics, and therapeutic modulation of autoantibodies against Sp100 and promyelocytic leukemia protein in a large cohort of patients with primary biliary cirrhosis. Hepatology 1997; 26: 1123.
- Corpechot C, Carrat F, Poujol-Robert A, et al. Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology 2012; 56: 198.
- Modena V, Marengo C, Amoroso A, et al. Primary biliary cirrhosis and rheumatic diseases: a clinical, immunological and immunogenetical study. Clin Exp Rheumatol 1986; 4: 129.
- Feizi T. Immunoglobulins in chronic liver disease. Gut 1968; 9: 193.
- Berg PA, Klein R. Antimitochondrial antibodies in primary biliary cirrhosis and other disorders: definition and clinical relevance. Dig Dis 1992; 10: 85.
- Czaja AJ, Carpenter HA, Manns MP. Antibodies to soluble liver antigen, P450IID6, and mitochondrial complexes in chronic hepatitis. Gastroenterology 1993; 105: 1522.
- Munoz LE, Thomas HC, Scheuer PJ, et al. Is mitochondrial antibody diagnostic of primary biliary cirrhosis? Gut 1981; 22: 136.
- Leung PS, Rossaro L, Davis PA, et al. Antimitochondrial antibodies in acute liver failure: implications for primary biliary cirrhosis. Hepatology 2007; 46: 1436.
- Metcalf JV, Mitchison HC, Palmer JM, et al. Natural history of early primary biliary cirrhosis. Lancet 1996; 348: 1399.
- Assassi S, Fritzler MJ, Arnett FC, et al. Primary biliary cirrhosis (PBC), PBC autoantibodies, and hepatic parameter abnormalities in a large population of systemic sclerosis patients. J Rheumatol 2009; 36: 2250.
- Ludwig J, Dickson ER, McDonald GS. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol 1978; 379: 103.
- Scheuer P. Primary biliary cirrhosis. Proc R Soc Med 1967; 60: 1257.
- Goldin RD. Diagnosis of biliary ductopaenia. Histopathology 1997; 31: 397.
- Jain S, Scheuer PJ, Archer B, et al. Histological demonstration of copper and copper-associated protein in chronic liver diseases. J Clin Pathol 1978; 31: 784.
- Zein CO, Angulo P, Lindor KD. When is liver biopsy needed in the diagnosis of primary biliary cirrhosis? Clin Gastroenterol Hepatol 2003; 1: 89.
- Wong RK, Lim SG, Wee A, et al. Primary biliary cirrhosis in Singapore: evaluation of demography, prognostic factors and natural course in a multi-ethnic population. J Gastroenterol Hepatol 2008; 23: 599.
- Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology 2009; 50: 291.
- Tsuji K, Watanabe Y, Van De Water J, et al. Familial primary biliary cirrhosis in Hiroshima. J Autoimmun 1999; 13: 171.
- Kar SP, Seldin MF, Chen W, et al. Pathway-based analysis of primary biliary cirrhosis genome-wide association studies. Genes Immun 2013; 14: 179.
- Robson SC, Hift RJ, Kirsch RE. Primary biliary cirrhosis. A retrospective survey at Groote Schuur Hospital, Cape Town. S Afr Med J 1990; 78: 19.
- Lucey MR, Neuberger JM, Williams R. Primary biliary cirrhosis in men. Gut 1986; 27: 1373.
- Anand AC, Elias E, Neuberger JM. End-stage primary biliary cirrhosis in a first generation migrant south Asian population. Eur J Gastroenterol Hepatol 1996; 8: 663.
- Al-Harthy N, Kumagi T, Coltescu C, et al. The specificity of fatigue in primary biliary cirrhosis: evaluation of a large clinic practice. Hepatology 2010; 52: 562.
- Zukowski TH, Jorgensen RA, Dickson ER, et al. Autoimmune conditions associated with primary biliary cirrhosis: response to ursodeoxycholic acid therapy. Am J Gastroenterol 1998; 93: 958.
- Pares A, Bruguera M, Rodes J. Renal tubular damage depresses renal uric acid excretion in primary biliary cirrhosis. Hepatology 1984; 4: 1265.
- Powell FC, Schroeter AL, Dickson ER. Primary biliary cirrhosis and the CREST syndrome: a report of 22 cases. Q J Med 1987; 62: 75.
- Mills P, MacSween RN, Watkinson G. Arthritis and primary biliary cirrhosis. Br Med J 1977; 2: 1224.
- Mills PR, Vallance R, Birnie G, et al. A prospective survey of radiological bone and joint changes in primary biliary cirrhosis. Clin Radiol 1981; 32: 297.
- Esquivel CO, Van Thiel DH, Demetris AJ, et al. Transplantation for primary biliary cirrhosis. Gastroenterology 1988; 94: 1207.
- Pereira SP, Bray GP, Pitt PI, et al. Non-invasive assessment of bone density in primary biliary cirrhosis. Eur J Gastroenterol Hepatol 1999; 11: 323.
- Hodgson SF, Dickson ER, Eastell R, et al. Rates of cancellous bone remodeling and turnover in osteopenia associated with primary biliary cirrhosis. Bone 1993; 14: 819.
- Krowka MJ, Grambsch PM, Edell ES, et al. Primary biliary cirrhosis: relation between hepatic function and pulmonary function in patients who never smoked. Hepatology 1991; 13: 1095.
- Keeffe EB. Sarcoidosis and primary biliary cirrhosis. Literature review and illustrative case. Am J Med 1987; 83: 977.
- Yap SH, Schillings PH, Van Tongeren JH. Acute interstitial pneumonia (fibrosing alveolitis) in a patient with primary biliary cirrhosis. Neth J Med 1980; 23: 111.
- Strobel ES, Bonnet RB, Werner P, et al. Bronchiolitis obliterans organising pneumonia and primary biliary cirrhosis-like lung involvement in a patient with primary biliary cirrhosis. Clin Rheumatol 1998; 17: 246.
- Butler P, Hamilton-Miller JM, McIntyre N, et al. Natural history of bacteriuria in women with primary biliary cirrhosis and the effect of antimicrobial therapy in symptomatic and asymptomatic groups. Gut 1995; 36: 931.
- Islam S, Riordan JW, McDonald JA. Case report: a rare association of primary biliary cirrhosis and systemic lupus erythematosus and review of the literature. J Gastroenterol Hepatol 1999; 14: 431.
- Gagnerie F, Taillan B, Euller-Ziegler L, et al. Primary biliary cirrhosis, temporal arteritis (giant cell arteritis) and polymyalgia rheumatica in a single patient. Scand J Rheumatol 1988; 17: 231.
- Rai GS, Hamlyn AN, Dahl MG, et al. Primary biliary cirrhosis, cutaneous capillaritis, and IgM-associated membranous glomerulonephritis. Br Med J 1977; 1: 817.
- Tsai WC, Matsumura K, Sonoo M, et al. [Dystrophin abnormality in a patient with polymyositis associated with primary biliary cirrhosis and myocardial injury]. Rinsho Shinkeigaku 1996; 36: 876.
- Dickey W, McMillan SA, Callender ME. High prevalence of celiac sprue among patients with primary biliary cirrhosis. J Clin Gastroenterol 1997; 25: 328.
- Sjoberg K, Lindgren S, Eriksson S. Frequent occurrence of non-specific gliadin antibodies in chronic liver disease. Endomysial but not gliadin antibodies predict coeliac disease in patients with chronic liver disease. Scand J Gastroenterol 1997; 32: 1162.
- Lofgren J, Jarnerot G, Danielsson D, et al. Incidence and prevalence of primary biliary cirrhosis in a defined population in Sweden. Scand J Gastroenterol 1985; 20: 647.
- Nijhawan PK, Therneau TM, Dickson ER, et al. Incidence of cancer in primary biliary cirrhosis: the Mayo experience. Hepatology 1999; 29: 1396.
- Howel D, Metcalf JV, Gray J, et al. Cancer risk in primary biliary cirrhosis: a study in northern England. Gut 1999; 45: 756.
- Wee A, Ludwig J. Pericholangitis in chronic ulcerative colitis: primary sclerosing cholangitis of the small bile ducts? Ann Intern Med 1985; 102: 581.
- J Ludwig, KP Batts (eds). Practical Liver Biopsy Interpretation, 2nd edn. Chicago: American Society of Clinical Pathologists; 1998.
- Chia SC, Bergasa NV, Kleiner DE, et al. Pruritus as a presenting symptom of chronic hepatitis C. Dig Dis Sci 1998; 43: 2177.
- Zimmerman HJ. Hepatotoxicity, 2nd edn. Philadelphia: Lippincott Williams & Wilkins; 1999.
- Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999; 31: 929.
- Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008; 48: 169.
- Chazouilleres O, Wendum D, Serfaty L, et al. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology 1998; 28: 296.
- Invernizzi P, Crosignani A, Battezzati PM, et al. Comparison of the clinical features and clinical course of antimitochondrial antibody-positive and -negative primary biliary cirrhosis. Hepatology 1997; 25: 1090.
- Kim WR, Poterucha JJ, Jorgensen RA, et al. Does antimitochondrial antibody status affect response to treatment in patients with primary biliary cirrhosis? Outcomes of ursodeoxycholic acid therapy and liver transplantation. Hepatology 1997; 26: 22.
- Gisbert JP, Jones EA, Pajares JM, et al. Review article: is there an optimal therapeutic regimen for antimitochondrial antibody-negative primary biliary cirrhosis (autoimmune cholangitis). Aliment Pharmacol Ther 2003; 17: 17.
- Tsuneyama K, Van De Water J, Van Thiel D, et al. Abnormal expression of PDC-E2 on the apical surface of biliary epithelial cells in patients with antimitochondrial antibody-negative primary biliary cirrhosis. Hepatology 1995; 22: 1440.
- Mayo MJ, Lipsky PE, Miller SN, et al. Similar T-cell oligoclonality in antimitochondrial antibody-positive and -negative primary biliary cirrhosis. Dig Dis Sci 2001; 46: 345.
- Krzeski P, Zych W, Kraszewska E, et al. Is serum bilirubin concentration the only valid prognostic marker in primary biliary cirrhosis? Hepatology 1999; 30: 865.
- Mahl TC, Shockcor W, Boyer JL. Primary biliary cirrhosis: survival of a large cohort of symptomatic and asymptomatic patients followed for 24 years. J Hepatol 1994; 20: 707.
- Prince M, Chetwynd A, Newman W, et al. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology 2002; 123: 1044.
- Dickson ER, Grambsch PM, Fleming TR, et al. Prognosis in primary biliary cirrhosis: model for decision making. Hepatology 1989; 10: 1.
- Christensen E, Altman DG, Neuberger J, et al. Updating prognosis in primary biliary cirrhosis using a time-dependent Cox regression model. PBC1 and PBC2 trial groups. Gastroenterology 1993; 105: 1865.
- Shapiro JM, Smith H, Schaffner F. Serum bilirubin: a prognostic factor in primary biliary cirrhosis. Gut 1979; 20: 137.
- Jones EA, Bergasa NV. The pruritus of cholestasis. Hepatology 1999; 29: 1003.
- Heathcote EJ, Cauch-Dudek K, Walker V, et al. The Canadian multicenter double-blind randomized controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1994; 19: 1149.
- Poupon RE, Poupon R, Balkau B. Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study Group. N Engl J Med 1994; 330: 1342.
- Leuschner U. Primary biliary cirrhosis–presentation and diagnosis. Clin Liver Dis 2003; 7: 741.
- Trauner M, Graziadei IW. Review article: mechanisms of action and therapeutic applications of ursodeoxycholic acid in chronic liver diseases. Aliment Pharmacol Ther 1999; 13: 979.
- Lindor KD, Dickson ER, Baldus WP, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology 1994; 106: 1284.
- Combes B, Carithers RL Jr, Maddrey WC, et al. A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1995; 22: 759.
- Pares A, Caballeria L, Rodes J, et al. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver. J Hepatol 2000; 32: 561.
- Poupon RE, Lindor KD, Cauch-Dudek K, et al. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997; 113: 884.
- Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet 1999; 354: 1053.
- Gluud C, Christensen E. Ursodeoxycholic acid for primary biliary cirrhosis: lesson for the future? J Hepatol 2001; 34: 787.
- Papatheodoridis GV, Hadziyannis ES, Deutsch M, et al. Ursodeoxycholic acid for primary biliary cirrhosis: final results of a 12-year, prospective, randomized, controlled trial. Am J Gastroenterol 2002; 97: 2063.
- Corpechot C, Carrat F, Poupon R, et al. Primary biliary cirrhosis: incidence and predictive factors of cirrhosis development in ursodiol-treated patients. Gastroenterology 2002; 122: 652.
- Corpechot C, Carrat F, Bahr A, et al. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology 2005; 128: 297.
- Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology 2006; 130: 715.
- Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 2008; 48: 871.
- Rautiainen H, Karkkainen P, Karvonen AL, et al. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology 2005; 41: 747.
- Hoofnagle JH, Davis GL, Schafer DF, et al. Randomized trial of chlorambucil for primary biliary cirrhosis. Gastroenterology 1986; 91: 1327.
- Bodenheimer HC Jr, Schaffner F, Sternlieb I, et al. A prospective clinical trial of D-penicillamine in the treatment of primary biliary cirrhosis. Hepatology 1985; 5: 1139.
- Dickson ER, Fleming TR, Wiesner RH, et al. Trial of penicillamine in advanced primary biliary cirrhosis. N Engl J Med 1985; 312: 1011.
- Neuberger J, Christensen E, Portmann B, et al. Double blind controlled trial of d-penicillamine in patients with primary biliary cirrhosis. Gut 1985; 26: 114.
- Lombard M, Portmann B, Neuberger J, et al. Cyclosporin A treatment in primary biliary cirrhosis: results of a long-term placebo controlled trial. Gastroenterology 1993; 104: 519.
- Christensen E, Neuberger J, Crowe J, et al. Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis. Final results of an international trial. Gastroenterology 1985; 89: 1084.
- Heathcote J, Ross A, Sherlock S. A prospective controlled trial of azathioprine in primary biliary cirrhosis. Gastroenterology 1976; 70: 656.
- Kaplan MM, Alling DW, Zimmerman HJ, et al. A prospective trial of colchicine for primary biliary cirrhosis. N Engl J Med 1986; 315: 1448.
- Warnes TW, Smith A, Lee FI, et al. A controlled trial of colchicine in primary biliary cirrhosis. Trial design and preliminary report. J Hepatol 1987; 5: 1.
- Bodenheimer H Jr, Schaffner F, Pezzullo J. Evaluation of colchicine therapy in primary biliary cirrhosis. Gastroenterology 1988; 95: 124.
- Gong Y, Gluud C. Colchicine for primary biliary cirrhosis. Cochrane Database Syst Rev 2004;(2):CD004481.
- Combes B, Emerson SS, Flye NL, et al. Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology 2005; 42: 1184.
- Talwalkar JA, Angulo P, Keach JC, et al. Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid. J Clin Gastroenterol 2005; 39: 168.
- Angulo P, Patel T, Jorgensen RA, et al. Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 2000; 32: 897.
- Mitchison HC, Palmer JM, Bassendine MF, et al. A controlled trial of prednisolone treatment in primary biliary cirrhosis. Three-year results. J Hepatol 1992; 15: 336.
- Angulo P, Jorgensen RA, Keach JC, et al. Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 2000; 31: 318.
- Leuschner M, Maier KP, Schlichting J, et al. Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial. Gastroenterology 1999; 117: 918.
- Trauner MI, Halilbasic E, Kazemi-Shirazi L, et al. Therapeutic role of bile acids and nuclear receptor agonists in fibrosing cholangiopathies. Dig Dis 2014; 32: 631.
- Levy C, Peter JA, Nelson DR, et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment Pharmacol Ther 2011; 33: 235.
- Sylvestre PB, Batts KP, Burgart LJ, et al. Recurrence of primary biliary cirrhosis after liver transplantation: histologic estimate of incidence and natural history. Liver Transpl 2003; 9: 1086.
- Ghent CN, Carruthers SG. Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial. Gastroenterology 1988; 94: 488.
- Podesta A, Lopez P, Terg R, et al. Treatment of pruritus of primary biliary cirrhosis with rifampin. Dig Dis Sci 1991; 36: 216.
- Bachs L, Pares A, Elena M, et al. Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis. Lancet 1989; 1: 574.
- Mayo MJ, Handem I, Saldana S, et al. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology 2007; 45: 666.
- Schworer H, Hartmann H, Ramadori G. Relief of cholestatic pruritus by a novel class of drugs: 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists: effectiveness of ondansetron. Pain 1995; 61: 33.
- O'Donohue JW, Pereira SP, Ashdown AC, et al. A controlled trial of ondansetron in the pruritus of cholestasis. Aliment Pharmacol Ther 2005; 21: 1041.
- Theal JJ, Toosi MN, Girlan L, et al. A randomized, controlled crossover trial of ondansetron in patients with primary biliary cirrhosis and fatigue. Hepatology 2005; 41: 1305.
- Prince MI, Mitchison HC, Ashley D, et al. Oral antioxidant supplementation for fatigue associated with primary biliary cirrhosis: results of a multicentre, randomized, placebo-controlled, cross-over trial. Aliment Pharmacol Ther 2003; 17: 137.
- ter Borg PC, van Os E, van den Broek WW, et al. Fluvoxamine for fatigue in primary biliary cirrhosis and primary sclerosing cholangitis: a randomised controlled trial [ISRCTN88246634]. BMC Gastroenterol 2004; 4: 13.
- Rong G, Zhou Y, Xiong Y, et al. Imbalance between T helper type 17 and T regulatory cells in patients with primary biliary cirrhosis: the serum cytokine profile and peripheral cell population. Clin Exp Immunol 2009; 156: 217.
- Menon KV, Angulo P, Boe GM, et al. Safety and efficacy of estrogen therapy in preventing bone loss in primary biliary cirrhosis. Am J Gastroenterol 2003; 98: 889.
- Levy C, Harnois DM, Angulo P, et al. Raloxifene improves bone mass in osteopenic women with primary biliary cirrhosis: results of a pilot study. Liver Int 2005; 25: 117.
- Guanabens N, Pares A, Ros I, et al. Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis. Am J Gastroenterol 2003; 98: 2268.
- Zein CO, Jorgensen RA, Clarke B, et al. Alendronate improves bone mineral density in primary biliary cirrhosis: a randomized placebo-controlled trial. Hepatology 2005; 42: 762.
- Guanabens N, Pares A, del Rio L, et al. Sodium fluoride prevents bone loss in primary biliary cirrhosis. J Hepatol 1992; 15: 345.
- Crippin JS, Lindor KD, Jorgensen R, et al. Hypercholesterolemia and atherosclerosis in primary biliary cirrhosis: what is the risk? Hepatology 1992; 15: 858.
- Van Dam GM, Gips CH. Primary biliary cirrhosis in The Netherlands. An analysis of associated diseases, cardiovascular risk, and malignancies on the basis of mortality figures. Scand J Gastroenterol 1997; 32: 77.
- Schaffner F. Paradoxical elevation of serum cholesterol by clofibrate in patients with primary biliary cirrhosis. Gastroenterology 1969; 57: 253.
- Kurihara T, Akimoto M, Abe K, et al. Experimental use of pravastatin in patients with primary biliary cirrhosis associated with hypercholesterolemia. Clin Ther 1993; 15: 890.
- Ritzel U, Leonhardt U, Nather M, et al. Simvastatin in primary biliary cirrhosis: effects on serum lipids and distinct disease markers. J Hepatol 2002; 36: 454.
- Kojima S, Toyota Y, Shiba M, et al. Different apheresis methods in the treatment of hypercholesterolemia in primary biliary cirrhosis: a case report. Artif Organs 1995; 19: 938.
- Joshi S, Cauch-Dudek K, Wanless IR, et al. Primary biliary cirrhosis with additional features of autoimmune hepatitis: response to therapy with ursodeoxycholic acid. Hepatology 2002; 35: 409.
- Gunsar F, Akarca US, Ersoz G, et al. Clinical and biochemical features and therapy responses in primary biliary cirrhosis and primary biliary cirrhosis-autoimmune hepatitis overlap syndrome. Hepatogastroenterology 2002; 49: 1195.
