Rheumatoid Arthritis and Primary Biliary Cirrhosis: Cause, Consequence, or Coincidence?

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease characterized serologically by cholestasis and the presence of high-titre antimitochondrial antibodies and histologically by chronic nonsuppurative cholangitis and granulomata. PBC patients often have concomitant autoimmune diseases, including arthropathies. This raises the question as to whether there are shared features in the pathogenesis of those diseases with the pathogenesis of PBC. Epidemiological and large case studies have indicated that although the incidence of rheumatoid arthritis (RA) is not significantly raised in PBC patients, there appears to be a higher rate of RA in PBC patients and their relatives. Genetic studies have demonstrated that several genes implicated in PBC have also been implicated in RA. Epigenetic studies provided a wealth of data regarding RA, but the findings on epigenetic changes in PBC are very limited. As well, certain infectious agents identified in the pathogenesis of PBC may also play a role in the pathogenesis of RA. These data suggest that although RA is not significantly present in PBC, some individuals with certain genetic traits and environmental exposures may develop both conditions. This concept may also apply to other concomitant diseases found in PBC patients.

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Twelve-Year-Old Girl with Primary Biliary Cirrhosis

Case Reports in Pediatrics ◽

10.1155/2012/937150 ◽

2012 ◽

Vol 2012 ◽

pp. 1-3 ◽

Cited By ~ 1

Author(s):

Ivana Kitic ◽

Aleksandra Boskovic ◽

Ivica Stankovic ◽

Dragan Prokic

Keyword(s):

Primary Biliary Cirrhosis ◽

World Literature ◽

Pediatric Patients ◽

Immunoglobulin M ◽

Cholestatic Liver Disease ◽

Biliary Cirrhosis ◽

Antimitochondrial Antibodies ◽

Biochemical Tests ◽

Autoimmune Etiology

Primary biliary cirrhosis (PBC) is a slowly progressive cholestatic liver disease of autoimmune etiology. The initial presentation of PBC is varies from asymptomatic, abnormal liver biochemical tests to overt cirrhosis. Unlike other autoimmune liver diseases, PBC has rarely been reported in childhood. We report a case of primary biliary cirrhosis in a 12-year-old girl. In addition to characteristic histology features, strongly positive antimitochondrial antibodies, increased liver enzyme levels, increased serum quantitative immunoglobulin M levels, and cholestasis were discovered. She had been treated with ursodeoxycholic acid. In the world literature, we found only few pediatric patients of primary biliary cirrhosis. Aetiology, pathogenesis, the long-term natural history, and prognosis remain obscure. Due to increased awareness of early-onset PBC, rather than typical older ones, further pediatric cases may be discovered.

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Infectious Agents and Xenobiotics in the Etiology of Primary Biliary Cirrhosis

Disease Markers ◽

10.1155/2010/752314 ◽

2010 ◽

Vol 29 (6) ◽

pp. 287-299 ◽

Cited By ~ 28

Author(s):

Carlo Selmi ◽

Maria De Santis ◽

Francesca Cavaciocchi ◽

M. Eric Gershwin

Keyword(s):

Primary Biliary Cirrhosis ◽

Latitudinal Gradient ◽

Monozygotic Twins ◽

Review Article ◽

Mitochondrial Proteins ◽

Cholestatic Liver Disease ◽

Biliary Cirrhosis ◽

Infectious Agents ◽

Environmental Stimulation ◽

High Concordance

Primary biliary cirrhosis (PBC)is a chronic autoimmune cholestatic liver disease that manifests a latitudinal gradient in prevalence and incidence. The mechanisms leading to the initiation and perpetuation of PBC remain largely enigmatic, although it is established that a combination of genetic predisposition and environmental stimulation is required. PBC is also characterized by a high concordance rate in monozygotic twins and is considered a model autoimmune disease because of several features common to other conditions and the relatively homogeneous serological and biochemical features. From a diagnostic standpoint, PBC is characterized by the highest specificity of serum autoantibodies directed at mitochondrial proteins. Several risk factors have been suggested to be associated with PBC, including exposure to infectious agents and chemical xenobiotics that will be critically discussed in the present review article.

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Tuberculosis Is Not a Risk Factor for Primary Biliary Cirrhosis: A Review of the Literature

Tuberculosis Research and Treatment ◽

10.1155/2012/218183 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10

Author(s):

Daniel S. Smyk ◽

Dimitrios P. Bogdanos ◽

Albert Pares ◽

Christos Liaskos ◽

Charalambos Billinis ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Primary Biliary Cirrhosis ◽

Causal Relation ◽

Association Studies ◽

Epidemiologic Studies ◽

High Titre ◽

Molecular Evidence ◽

Cholestatic Liver Disease ◽

Biliary Cirrhosis ◽

Genome Wide Association Studies

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease characterised serologically by cholestasis and the presence of high-titre antimitochondrial antibodies, and histologically by chronic nonsuppurative cholangitis and granulomata. As PBC is a granulomatous disease andMycobacterium tuberculosisis the most frequent cause of granulomata, a causal relation between tuberculosis and PBC has been suggested. Attempts to find serological evidence of PBC-specific autoantibodies such as AMA have been made and, conversely, granulomatous livers from patients with PBC have been investigated for molecular evidence ofMycobacterium tuberculosis. This paper discusses in detail the reported data in support or against an association betweenMycobacterium tuberculosisinfection and PBC. We discuss the immunological and microbiological data exploring the association of PBC with exposure toMycobacterium tuberculosis. We also discuss the findings of large epidemiologic studies investigating the association of PBC with preexistent or concomitant disorders and the relevance of these findings with tuberculosis. Genome-wide association studies in patients with tuberculosis as well as in patients with PBC provide conclusive hints regarding the assumed association between exposure to this mycobacterium and the induction of PBC. Analysis of these data suggest thatMycobacterium tuberculosisis an unlikely infectious trigger of PBC.

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Oral Tolerance and Pyruvate Dehydrogenase in Patients with Primary Biliary Cirrhosis

Developmental Immunology ◽

10.1080/1044667021000098561 ◽

2002 ◽

Vol 9 (2) ◽

pp. 55-61 ◽

Cited By ~ 6

Author(s):

Ayako Suzuki ◽

Judy van de Water ◽

M. Eric Gershwin ◽

Roberta Jorgensen ◽

Paul Angulo ◽

...

Keyword(s):

Primary Biliary Cirrhosis ◽

Pyruvate Dehydrogenase ◽

Oral Tolerance ◽

Early Stage ◽

Pyruvate Dehydrogenase Complex ◽

Tolerance Induction ◽

Cholestatic Liver Disease ◽

Biliary Cirrhosis ◽

Antimitochondrial Antibodies ◽

Immunological Destruction

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by the immunological destruction of intralobular bile ducts and serum anti-mitochondrial antibodies (AMA). Based upon previous work of oral tolerance and autoimmunity, we hypothesized that feeding the mitochondrial autoantigens of PBC would alter the clinical course and the level of antimitochondrial antibodies. The bovine pyruvate dehydrogenase complex (PDC) was purified and 5 mg fed in gelatin capsules to 6 patients with early stage PBC for 6 months. Antimitochondrial antibodies and liver biochemistries were measured at every 3 months for 12 months. The clinical trial was completed for all patients except for 1 who showed deterioration of pre-existing skin rash during treatment, which disappeared within 2 weeks after treatment was discontinued. However, after 1 year, neither the titers of AMAs nor liver biochemistries were significantly changed by this treatment. This is the first trial to test the efficacy of oral tolerance induction in PBC. However, the data, which limited in scope, did not demonstrate efficacy and further highlights the difficulties in showing continuing evidence of tolerance induction in autoimmunity.

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Sex Differences Associated with Primary Biliary Cirrhosis

Clinical and Developmental Immunology ◽

10.1155/2012/610504 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 17

Author(s):

Daniel S. Smyk ◽

Eirini I. Rigopoulou ◽

Albert Pares ◽

Charalambos Billinis ◽

Andrew K. Burroughs ◽

...

Keyword(s):

Primary Biliary Cirrhosis ◽

Clinical Course ◽

Epidemiological Studies ◽

Cholestatic Liver Disease ◽

Biliary Cirrhosis ◽

Antimitochondrial Antibodies ◽

Intrahepatic Bile Ducts ◽

Life Threatening ◽

Low Incidence ◽

Disease Specific

Primary biliary cirrhosis (PBC) is a cholestatic liver disease of autoimmune origin, characterised by the destruction of small intrahepatic bile ducts. The disease has an unpredictable clinical course but may progress to fibrosis and cirrhosis. The diagnostic hallmark of PBC is the presence of disease-specific antimitochondrial antibodies (AMA), which are pathognomonic for the development of PBC. The disease overwhelmingly affects females, with some cases of male PBC being reported. The reasons underlying the low incidence of males with PBC are largely unknown. Epidemiological studies estimate that approximately 7–11% of PBC patients are males. There does not appear to be any histological, serological, or biochemical differences between male and female PBC, although the symptomatology may differ, with males being at higher risk of life-threatening complications such as gastrointestinal bleeding and hepatoma. Studies on X chromosome and sex hormones are of interest when studying the low preponderance of PBC in males; however, these studies are far from conclusive. This paper will critically analyze the literature surrounding PBC in males.

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Environmental Agents Involved in the Cause of Primary Biliary Cirrhosis

Disease Markers ◽

10.1155/2010/824396 ◽

2010 ◽

Vol 29 (6) ◽

pp. 329-336 ◽

Cited By ~ 1

Author(s):

Elias Kouroumalis

Keyword(s):

Primary Biliary Cirrhosis ◽

Environmental Factors ◽

Monozygotic Twins ◽

Cholestatic Liver Disease ◽

Biliary Cirrhosis ◽

Infectious Agents ◽

Immune Mediated ◽

Environmental Agents ◽

Autoimmune Conditions ◽

Genetic And Environmental Factors

Primary biliary cirrhosis (PBC) is an immune mediated chronic cholestatic liver disease with a slowly progressive course It is a universal disease with a reported latitudinal gradient in prevalence and incidence. The aetiology of primary biliary cirrhosis is still unknown. It is characterized by a 60% concordance in monozygotic twins and is considered an autoimmune disease because of several features common to other autoimmune conditions and the relatively homogeneous serological and biochemical features. However geoepidemiological and clinical studies strongly imply that environmental factors also play an important role. It is accepted that the disease is clearly the result of a combination of genetic and environmental factors. Several risk factors have been suggested to be associated with PBC, including exposure to infectious agents and chemical xenobiotics. This review will attempt to place such factors in perspective.

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Infection as a Risk Factor in the Pathogenesis of Primary Biliary Cirrhosis: Pros and Cons

Disease Markers ◽

10.1155/2010/791310 ◽

2010 ◽

Vol 29 (6) ◽

pp. 313-321 ◽

Cited By ~ 6

Author(s):

Teru Kumagi ◽

Masanori Abe ◽

Yoshiou Ikeda ◽

Yoichi Hiasa

Keyword(s):

Primary Biliary Cirrhosis ◽

Environmental Factors ◽

Molecular Mimicry ◽

Cholestatic Liver Disease ◽

Biliary Cirrhosis ◽

Infectious Agents ◽

Case Control Studies ◽

Intrahepatic Bile Ducts ◽

Genome Wide ◽

Pros And Cons

Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology, characterized by injury of the intrahepatic bile ducts that may eventually lead to cirrhosis and liver failure. Evidence suggests cardinal roles for both environmental factors and genetic susceptibility. Nevertheless, the absolute etiology of PBC is unclear, despite recent well-designed case-control studies that reported environmental risk factors, including infectious agents, for PBC. Of the reported infectious agents, some of them are not reproducible and remain controversial. However, infection is no doubt one of the major risks among the environmental factors. This is supported by the fact that infectious agents in autoimmune diseases express antigens resulting in molecular mimicry and xenobiotics that play a role in breaking tolerance. Taken together, recent findings from genome wide assays as well as novel animal models may enable us to better understand the mechanism of pathogenesis responsible for this disease.

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Infectious Agents in the Pathogenesis of Primary Biliary Cirrhosis

Disease Markers ◽

10.1155/2010/923928 ◽

2010 ◽

Vol 29 (6) ◽

pp. 277-286 ◽

Cited By ~ 13

Author(s):

Oscar-Danilo Ortega-Hernandez ◽

Nancy-Agmon Levin ◽

Arie Altman ◽

Yehuda Shoenfeld

Keyword(s):

Primary Biliary Cirrhosis ◽

Pyruvate Dehydrogenase ◽

Molecular Mimicry ◽

Pyruvate Dehydrogenase Complex ◽

Amino Acid Sequences ◽

Molecular Evidence ◽

Cholestatic Liver Disease ◽

Biliary Cirrhosis ◽

Infectious Agents ◽

Autoimmune Process

Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease which is characterized by the breakdown of self-tolerance to the highly conserved pyruvate dehydrogenase complex, specially the pyruvate dehydrogenase E2 complex (PDC-E2). The breakdown of the tolerance to such antigens leads to an autoimmune process characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. Epidemiological studies have suggested that infections agents can trigger or even exacerbate the disease. Among other gram negative bacteria,Escherichia Coli, andNosphingobium aromaticivoransare the most associated agents reported hitherto. Epidemiological and molecular evidence points towards molecular mimicry between some components of these microorganisms and specific amino-acid sequences that are present in proteins on normal cells of the biliary tract. In this review, we revisit all reports suggesting that infectious agents might be associated with the autoimmune pathogenesis of PBC. We also retrieve the immune molecular mimicry mechanisms that are likely involved with the autoimmune process in PBC.

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A novel etiologic factor of highly elevated cholestanol levels: progressive familial intrahepatic cholestasis

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0314 ◽

2020 ◽

Vol 33 (5) ◽

pp. 665-669

Author(s):

Aynur Küçükçongar Yavaş ◽

Büşra Çavdarlı ◽

Özlem Ünal Uzun ◽

Ayşen Uncuoğlu ◽

Mehmet Gündüz

Keyword(s):

Primary Biliary Cirrhosis ◽

Intrahepatic Cholestasis ◽

Density Lipoprotein ◽

Etiologic Factor ◽

Compound Heterozygous ◽

Cholestatic Liver Disease ◽

Biliary Cirrhosis ◽

Progressive Familial Intrahepatic Cholestasis ◽

Turkish Patient ◽

Type 3

AbstractBackgroundProgressive familial intrahepatic cholestasis type 3 (PFIC3) is an uncommon cholestatic liver disease caused by mutations in the ATP binding cassette subfamily B member 4 (ABCB4) gene. Although PFIC3 is frequently identified in childhood, ABCB4 disease-causing alleles have been described in adults affected by intrahepatic cholestasis of pregnancy, hormone-induced cholestasis, low-phospholipid-associated cholelithiasis syndrome or juvenile cholelithiasis, cholangiocarcinoma and in sporadic forms of primary biliary cirrhosis. Cholestanol is a biomarker which is elevated especially in cerebrotendinous xanthomatosis and rarely in primary biliary cirrhosis (PBC) and Niemann Pick type C.Case presentationHere we report a Turkish patient with compound heterozygous mutations in the ABCB4 gene, who has hepatosplenomegaly, low level of high-density lipoprotein, cholestasis and high level of cholestanol.ConclusionThis is the first PFIC3 case with a high cholestanol level described in the literature. There are very few diseases linked to increased cholestanol levels, two of which are CTX and PBC. From this case, we can conclude that a high cholestanol level might be another indicator of PFIC type 3.

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