Primary Biliary Cirrhosis in a genetically homogeneous population: Disease associations and familial occurrence rates

BMC Gastroenterology

Elias A Kouroumalis³  Maria Tzardi¹  Aikaterini Darivianaki²  Jean Marie Enele-Melono³  Gregory Chlouverakis⁴  Mairi Koulentaki³  Aikaterini Mantaka³ 

[1] Department of Pathology, University Hospital of Heraklion, PO BOX 1352, Heraklion, 71100, Crete, Greece;Department of Clinical Immunology, University Hospital of Heraklion, PO BOX 1352, Heraklion, 71100, Crete, Greece;Department of Gastroenterology and Hepatology, University Hospital of Heraklion, P.O. BOX 1352, Heraklion, 71100, Crete, Greece;Department of Social Medicine, Faculty of Medicine, University of Crete, Heraklion, 71100, Greece

关键词: educational level;    cancer;    dyslipidaemia;    cholecystectomy;    risk factors;    Familial pbc;   

Others  :  1121888
DOI  :  10.1186/1471-230X-12-110

 received in 2011-12-08, accepted in 2012-07-16,  发布年份 2012

【 摘 要 】

Background

Primary biliary cirrhosis (PBC) is a disease with genetic and environmental pathogenetic background. Chemicals, infectious agents, hormone therapy, reproductive history and surgical interventions have been implicated in the induction of PBC. Familial PBC has been documented in first degree relatives (FDR). Most cohort studies are genetically heterogeneous. Our study aimed to determine eventual lifestyle or disease associations and familial occurrence rates in a genetically homogeneous and geographically defined population of PBC patients.

Methods

111 consenting PBC patients, were compared with 115 FDR and 149 controls matched for age, sex, Cretan origin and residence. All participants completed a questionnaire regarding demographics, lifestyle, medical, surgical and reproductive history. Significant variables on the univariate analysis were analyzed by multivariate analysis using a forward step-wise logistic regression model.

Results

Dyslipidaemia was found in 69.4% of patients, 60% of FDR and 40.9% of controls (p < 0.0001 and p = 0.003 respectively), autoimmune diseases in 36.9% of patients, 30.4% of FDR and 13.4% of controls (p < 0.0001 and p = 0.011 respectively). Hashimoto’s disease (p = 0.003), Raynaud syndrome (p = 0.023) and Sjögren syndrome (p = 0.044) were significantly associated with PBC. On multivariate analysis statistically significant associations were found with primary educational level (AOR 2.304, 95% CI 1.024-5.181), cholecystectomy (AOR 2.927, 95% CI 1.347-6.362) and the presence of at least another autoimmune disease (AOR 3.318, 95% CI 1.177-6.22). Cancer history was more frequent in patients than in controls (p = 0.033). Familial PBC was found to be 9.9%.

Conclusions

Dyslipidaemia and autoimmune diseases were significantly increased not only in patients as expected but also in their FDR. An increased prevalence of malignancies was found in patients. Primary educational level, cholecystectomy and the presence of at least another autoimmune disease were found as putative risk factors for PBC. No association was found with smoking, urinary tract infection or reproductive history. The reported high familial occurrence of PBC could imply screening with AMA of FDR with at least another autoimmune disease.

【 授权许可】

   
2012 Mantaka et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Talwalkar JA, Lindor KD: Primary biliary cirrhosis. Lancet 2003, 362:53-61.
• [2]Poupon R: Primary biliary cirrhosis: A 2010 update. J Hepatol 2010, 52:745-58.
• [3]Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish RG, Gordon SC, Wright HI, Zweiban B, Podda M, Gershwin ME: Primary biliary cirrhosis in monozygotic and dizygotic twins: Genetics, epigenetics, and environment. Gastroenterology 2004, 127(2):485-92.
• [4]Corpechot C, Chritien Y, Chazouillieres O, Poupon R: Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis. J Hepatol 2010, 53:162-9.
• [5]Lazaridis KN, Juran BD, Boe GM, Slusser JP, de Andrade M, Homburger HA, Ghosh K, Dickson ER, Lindor KD, Petersen GM: Increased prevalence of antimitochondrial antibodies in first-degree relatives of patients with primary biliary cirrhosis. Hepatology 2007, 46:785-92.
• [6]Bogdanos DP, Smyk DS, Rigopoulou EI, Mytilinaiou MG, Heneghan MA, Selmi C: Eric Gershwin M. Twin studies in autoimmune disease: Genetics, gender and environment. J Autoimmun. 2012 May, 38:156-69.
• [7]Watt FE, James OFW, Jones DEJ: Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study. Q J M 2004, 97:397-406.
• [8]Prince MI, Chetwynd A, Diggle P, Jarner M, Metcalf JV, James OF: The geographical distribution of primary biliary cirrhosis in a well defined cohort. Hepatology 2001, 34:1083-8.
• [9]McNally RJ, Ducker S, James OF: Are transient environmental agents involved in the cause of primary biliary cirrhosis? Evidence from space-time clustering analysis. Hepatology 2009, 50:1169-74.
• [10]Ala A, Stanca CM, Bu-Ghanim M, Ahmado I, Branch AD, Schiano TD, Odin JA, Bach N: Increased prevalence of primary biliary cirrhosis near superfund toxic waste sites. Hepatology 2006, 43:525-31.
• [11]Jones DE: Pathogenesis of primary biliary cirrhosis. Gut 2007, 56:1615-24.
• [12]Bogdanos DP, Baum H, Grasso A, Okamoto M, Butler P, Ma Y, Rigopoulou E, Montalto P, Davies ET, Burroughs AK, Vergani D: Microbial mimics are major targets of cross-reactivity with human pyruvate dehydrogenase in primary biliary cirrhosis. J Hepatol. 2004 Jan, 40(1):31-9.
• [13]Vilagut L, Pares A, Vinas O, Vila J: Jiménez de Anta MT, Rodés J. Antibodies to mycobacterial 65kd heat shock protein cross react with the main mitochondrial antigens in patients with primary biliary cirrhosis. Eur J Clin Invest 1997, 27:667-72.
• [14]Klein R, Wiebel M, Engelhart S, Berg PA: Sera from patients with tuberculosis recognize the m2aepitope (e2subunit of pyruvate dehydrogenase) specific for primary biliary cirrhosis. Clin Exp Immunol 1993, 92:308-16.
• [15]Padgett KA, Selmi C, Kenny TP, Leung PS, Balkwill DL, Ansari AA, Coppel RL, Gershwin ME: Phylogenetic and immunological definition of four lipoylated proteins from novosphingobium aromaticivorans, implications for primary biliary cirrhosis. J Autoimmun 2005, 24:209-19.
• [16]Mattner J, Savage PB, Leung P, Oertelt SS, Wang V, Trivedi O, Scanlon ST, Pendem K, Teyton L, Hart J, Ridgway WM, Wicker LS, Gershwin ME, Bendelac A: Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell host Microbe 2008, 3(5):304-15.
• [17]Bogdanos LD, Pusl T, Rust C, Vergani D, Beuers U: Primary biliary cirrhosis following lactobacillus vaccination for recurrent vaginitis. J Hepatol 2008, 49:466-73.
• [18]Leung PS, Park O, Matsumura S, Ansari AA, Coppel RL, Gershwin ME: Is there a relation between Chlamydia infection and primary biliary cirrhosis? Clin Dev Immunol 2003, 10:227-33.
• [19]Abdulkarim AS, Petrovic LM, Kim WR, Angulo P, Lloyd RV, Lindor KD: Primary biliary cirrhosis: An infectious disease caused by chlamydia pneumoniae? J of Hepatol 2004, 40:380-84.
• [20]Boomkens SY, de Rave S, Pot RG, Egberink HF, Penning LC, Rothuizen J, Zondervan PE, Kusters JG: The role of helicobacter spp in the pathogenesis of primary biliary cirrhosis and primary sclerosing cholangitis. FEMS Immunol Med Microbiol 2005, 44:221-25.
• [21]Xu L, Shen Z, Guo L, Fodera B, Keogh A, Joplin R, O’Donnell B, Aitken J, Carman W, Neuberger J, Mason A: Does a beta retrovirus infection trigger primary biliary cirrhosis? Proc Nat Ac Sci USA 2003, 100:8454-9.
• [22]Mason A, Xu L, Shen Z, Fodera B, Joplin R, Neuberger J, O’Donnell B: Patients with primary biliary cirrhosis make antiviral and anti-mitochondrial antibodies to mouse mammary tumor virus. Gastroenterology 2004, 127(6):1863-4.
• [23]Long A, Quan C, Van de Water J, Nantz MH, Kurth MJ, Barsky D, Colvin ME, Lam KS, Coppel RL, Ansari A, Gershwin ME: Immunoreactivity of organic mimeotopes of the e2 component of pyruvate dehydrogenase: Connecting xenobiotics with primary biliary cirrhosis. J Immunol 2001, 167:2956-63.
• [24]Rieger R, Gershwin ME: The x and why of xenobiotics in primary biliary cirrhosis. J Autoimmun 2007, 28:76-84.
• [25]Prince MI, Ducker SJ, James OF: Case–control studies of risk factors for primary biliary cirrhosis in two United Kingdom populations. Gut 2010, 59(4):508-12.
• [26]Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, Lindor KD, Kaplan MM, Vierling JM: USA PBC Epidemiology Group. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology 2005, 42(5):1194-202.
• [27]Parikh-Patel A, Gold EB, Worman H, Krivy KE, Gershwin ME: Risk factors for primary biliary cirrhosis in a cohort of patients from the United States. Hepatology 2001, 33:16-21.
• [28]Tsuji K, Watanabe Y, Van De Water J, et al.: Familial primary biliary cirrhosis in Hiroshima. J Autoimmun 1999, 13:171-8.
• [29]Su TC, Hwang JJ, Kao JH: Hypercholesterolemia in primary biliary cirrhosis. N Engl J Med 2007, 357:1561-62.
• [30]Dudnik LB, Azyzova OA, Solovyova NP, Savchenkova AP, Pokrovskaya MA: Primary biliary cirrhosis and coronary atherosclerosis: protective antioxidant effect of bilirubin. Bull Exp Biol Med 2008, 145:18-22.
• [31]Floreani A, Variola A, Niro G, et al.: Plasma adiponectin levels in primary biliary cirrhosis: a novel perspective for link between hypercholesterolemia and protection against atherosclerosis. Am J Gastroenterol 2008, 103:1959-65.
• [32]Deutsch M, Papatheodoridis GV, Tzakou A, Hadziyannis SJ: Risk of hepatocellular carcinoma and extrahepatic malignancies in primary biliary cirrhosis. Eur J Gastroenterol Hepatol 2008, 20:5.