Primary biliary cirrhosis pathophysiology: Difference between revisions

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Latest revision as of 23:49, 29 July 2020

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Overview

Primary biliary cirrhosis also known as primary biliary cholangitis is an autoimmune cholestatic disease. The disease is chronic and slowly progressive. The exact pathogenesis of primary biliary cirrhosis is not fully understood. It is postulated that primary biliary cirrhosis is the result of antimitochondrial antibodies (AMAs), directed to the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Overexpression of Bcl-2 in small apoptotic biliary epithelial cells and cell lineage-specific lack of glutathione prevents loss of immunogenicity of the PDC-E2 component after apoptosis of biliary epithelial cells which finally results in autoimmunity. Primary biliary cirrhosis may be familial and is related to factors inherited maternally. Primary biliary cirrhosis is strongly associated with a variety of rheumatologic conditions, most commonly Sjogren's syndrome. On gross pathology, characteristic findings of primary biliary cirrhosis include hepatomegaly, splenomegaly, and cirrhosis (in late stage). On microscopic histopathological analysis, asymmetric destruction of the intralobular bile ducts within portal triads is characteristic findings of primary biliary cirrhosis.

Pathophysiology

Pathogenesis

The exact pathogenesis of primary biliary cirrhosis is not fully understood.
It is thought that primary biliary cirrhosis is the result of antimitochondrial antibodies (AMAs), directed to the E2 component of the pyruvate dehydrogenase complex (PDC-E2).^[1]

Algorithm showing postulated hypothesis of pathogenesis of primary biliary cirrhosis^[2]^[3]^[4]^[5]

Biliary epithelial cells (BEC)

Overexpression of Bcl-2 in small apoptotic BEC

Cell lineage specific lack of glutathione

Inhibition of PDC-E2 glutathiolation

Prevents loss of immunogenicity after apoptosis of BEC

PDC-E2 component remains intact and antigenic in apoptotic blebs of BEC

Antigenic PDC-E2 are engulfed by intrahepatic dendritic cells

Dendritic cells transfer antigenic PDC-E2 to regional lymph nodes

Antigenic PDC-E2 is recognized by MHC class I restricted CD8⁺ T cells

Initiates autoimmunity

Primary biliary cirrhosis

Genetics

Primary biliary cirrhosis may be familial and is related to factors inherited maternally.^[6]
Primary biliary cirrhosis tends to present at an earlier age in the second generation.

Associated Conditions

Conditions associated with primary biliary cirrhosis include:^[7]^[8]^[9]

Gross Pathology

On gross pathology, characteristic findings of primary biliary cirrhosis include:^[7]
- Hepatomegaly
- Splenomegaly
- Cirrhosis (late stages)

Microscopic Pathology

On microscopic histopathological analysis, asymmetric destruction of the intralobular bile ducts within portal triads is characteristic findings of primary biliary cirrhosis.
Primary biliary cirrhosis can be classified into four stages according to histological classification of Ludwig. According to Ludwig classification, all four stages may be present on a single liver biopsy.^[10]^[11]
It can also be classified into four stages according to the histological classification of P. Scheuer.^[12]

Classification of Primary biliary cirrhosis on the basis of histology
Stage	Histologic appearance
Stage	Ludwig classification	Scheuer's classification
Stage 1	Portal inflammation	Florid duct lesion or chronic non-suppurative destructive cholangitis
Stage 2	Extension of inflammation beyond portal tracts into surrounding parenchyma with or without ductal loss	Proliferation of the small bile ductules
Stage 3	Presence of fibrous septa linking adjacent portal tracts	Fibrosis or scarring
Stage 4	Cirrhosis	Cirrhosis

References

↑ Matsumura S, Van De Water J, Leung P, Odin JA, Yamamoto K, Gores GJ; et al. (2004). "Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis". Hepatology. 39 (5): 1415–22. doi:10.1002/hep.20175. PMID 15122771.
↑ Lleo A, Selmi C, Invernizzi P, Podda M, Coppel RL, Mackay IR; et al. (2009). "Apotopes and the biliary specificity of primary biliary cirrhosis". Hepatology. 49 (3): 871–9. doi:10.1002/hep.22736. PMC 2665925. PMID 19185000.
↑ Odin JA, Huebert RC, Casciola-Rosen L, LaRusso NF, Rosen A (2001). "Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis". J Clin Invest. 108 (2): 223–32. doi:10.1172/JCI10716. PMC 203018. PMID 11457875.
↑ Charlotte F, L'Herminé A, Martin N, Geleyn Y, Nollet M, Gaulard P; et al. (1994). "Immunohistochemical detection of bcl-2 protein in normal and pathological human liver". Am J Pathol. 144 (3): 460–5. PMC 1887102. PMID 8129031.
↑ Shimoda S, Harada K, Niiro H, Yoshizumi T, Soejima Y, Taketomi A; et al. (2008). "Biliary epithelial cells and primary biliary cirrhosis: the role of liver-infiltrating mononuclear cells". Hepatology. 47 (3): 958–65. doi:10.1002/hep.22102. PMID 18181218.
↑ Brind AM, Bray GP, Portmann BC, Williams R (1995). "Prevalence and pattern of familial disease in primary biliary cirrhosis". Gut. 36 (4): 615–7. PMC 1382507. PMID 7737573.
↑ ^7.0 ^7.1 Kumagi T, Heathcote EJ (2008). "Primary biliary cirrhosis". Orphanet J Rare Dis. 3: 1. doi:10.1186/1750-1172-3-1. PMC 2266722. PMID 18215315.
↑ Watt FE, James OF, Jones DE (2004). "Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study". QJM. 97 (7): 397–406. PMID 15208427.
↑ Tsianos EV, Hoofnagle JH, Fox PC, Alspaugh M, Jones EA, Schafer DF; et al. (1990). "Sjögren's syndrome in patients with primary biliary cirrhosis". Hepatology. 11 (5): 730–4. PMID 2347546.
↑ Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; et al. (2009). "Primary biliary cirrhosis". Hepatology. 50 (1): 291–308. doi:10.1002/hep.22906. PMID 19554543.
↑ Ludwig J, Dickson ER, McDonald GS (1978). "Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis)". Virchows Arch A Pathol Anat Histol. 379 (2): 103–12. PMID 150690.
↑ Scheuer P (1967). "Primary biliary cirrhosis". Proc R Soc Med. 60 (12): 1257–60. PMC 1901478. PMID 6066569.

Template:WH Template:WS

[pmid15122771-1] Matsumura S, Van De Water J, Leung P, Odin JA, Yamamoto K, Gores GJ; et al. (2004). "Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis". Hepatology. 39 (5): 1415–22. doi:10.1002/hep.20175. PMID 15122771.

[pmid19185000-2] Lleo A, Selmi C, Invernizzi P, Podda M, Coppel RL, Mackay IR; et al. (2009). "Apotopes and the biliary specificity of primary biliary cirrhosis". Hepatology. 49 (3): 871–9. doi:10.1002/hep.22736. PMC 2665925. PMID 19185000.

[pmid11457875-3] Odin JA, Huebert RC, Casciola-Rosen L, LaRusso NF, Rosen A (2001). "Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis". J Clin Invest. 108 (2): 223–32. doi:10.1172/JCI10716. PMC 203018. PMID 11457875.

[pmid8129031-4] Charlotte F, L'Herminé A, Martin N, Geleyn Y, Nollet M, Gaulard P; et al. (1994). "Immunohistochemical detection of bcl-2 protein in normal and pathological human liver". Am J Pathol. 144 (3): 460–5. PMC 1887102. PMID 8129031.

[pmid18181218-5] Shimoda S, Harada K, Niiro H, Yoshizumi T, Soejima Y, Taketomi A; et al. (2008). "Biliary epithelial cells and primary biliary cirrhosis: the role of liver-infiltrating mononuclear cells". Hepatology. 47 (3): 958–65. doi:10.1002/hep.22102. PMID 18181218.

[pmid7737573-6] Brind AM, Bray GP, Portmann BC, Williams R (1995). "Prevalence and pattern of familial disease in primary biliary cirrhosis". Gut. 36 (4): 615–7. PMC 1382507. PMID 7737573.

[pmid18215315-7] 7.0 ^7.1 Kumagi T, Heathcote EJ (2008). "Primary biliary cirrhosis". Orphanet J Rare Dis. 3: 1. doi:10.1186/1750-1172-3-1. PMC 2266722. PMID 18215315.

[pmid15208427-8] Watt FE, James OF, Jones DE (2004). "Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study". QJM. 97 (7): 397–406. PMID 15208427.

[pmid2347546-9] Tsianos EV, Hoofnagle JH, Fox PC, Alspaugh M, Jones EA, Schafer DF; et al. (1990). "Sjögren's syndrome in patients with primary biliary cirrhosis". Hepatology. 11 (5): 730–4. PMID 2347546.

[pmid19554543-10] Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; et al. (2009). "Primary biliary cirrhosis". Hepatology. 50 (1): 291–308. doi:10.1002/hep.22906. PMID 19554543.

[pmid150690-11] Ludwig J, Dickson ER, McDonald GS (1978). "Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis)". Virchows Arch A Pathol Anat Histol. 379 (2): 103–12. PMID 150690.

[pmid6066569-12] Scheuer P (1967). "Primary biliary cirrhosis". Proc R Soc Med. 60 (12): 1257–60. PMC 1901478. PMID 6066569.

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-{{Primary biliary cirrhosis}}
-{{CMG}}; {{AE}}
+{{CMG}}; {{AE}}{{Anmol}}
-{{PleaseHelp}}
 ==Overview==
+Primary biliary cirrhosis also known as primary biliary cholangitis is an [[autoimmune]] [[cholestatic]] disease. The disease is [[Chronic (medical)|chronic]] and slowly progressive. The exact pathogenesis of primary biliary cirrhosis is not fully understood. It is postulated that primary biliary cirrhosis is the result of [[antimitochondrial antibodies]] (AMAs), directed to the E2 component of the [[pyruvate dehydrogenase complex]] (PDC-E2). Overexpression of [[Bcl-2]] in small [[apoptotic]] [[biliary]] [[epithelial]] [[cells]] and cell lineage-specific lack of [[glutathione]] prevents loss of [[immunogenicity]] of the PDC-E2 component after [[apoptosis]] of biliary epithelial cells which finally results in [[autoimmunity]]. Primary biliary cirrhosis may be [[familial]] and is related to factors inherited maternally. Primary biliary cirrhosis is strongly associated with a variety of [[Rheumatology|rheumatologic]] conditions, most commonly [[Sjogren's syndrome]]. On gross pathology, characteristic findings of primary biliary cirrhosis include [[hepatomegaly]], [[splenomegaly]], and [[cirrhosis]] (in late stage). On [[microscopic]] [[histopathological]] analysis, asymmetric destruction of the [[Bile ducts|intralobular bile ducts]] within [[Portal triad|portal triads]] is characteristic findings of primary biliary cirrhosis.
 ==Pathophysiology==
-The pathogenesis of the disease is unknown at this time, but research indicates that there is an [[Immunology|immunological]] basis for the [[disease]], making it an [[autoimmune disorder]].  Most of the patients (>90%) seem to have anti-mitochondrial antibodies (AMAs) against [[pyruvate dehydrogenase complex]]  (PDC-E2), an enzyme complex that is found in the [[mitochondria]].
-In addition, a more specific test to confirm this disease from a bone disorder such as Paget's (disease of bone) which also has increases in alkaline phosphatase is the [[Gamma glutamyl transpeptidase|gamma-glutamyl trans peptidase]] test (GGTP). An increase in GGTP could indicate presence of primary biliary cirrhosis.
+===Pathogenesis===
+*The exact pathogenesis of primary biliary cirrhosis is not fully understood.
+*It is thought that primary biliary cirrhosis is the result of [[antimitochondrial antibodies]] (AMAs), directed to the E2 component of the [[pyruvate dehydrogenase complex]] (PDC-E2).<ref name="pmid15122771">{{cite journal| author=Matsumura S, Van De Water J, Leung P, Odin JA, Yamamoto K, Gores GJ et al.| title=Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis. | journal=Hepatology | year= 2004 | volume= 39 | issue= 5 | pages= 1415-22 | pmid=15122771 | doi=10.1002/hep.20175 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15122771  }} </ref>
-% of patients with acute liver failure have [[anti-transglutaminase antibodies]]<ref name="pmid17657817">{{cite journal | author = Leung PS, Rossaro L, Davis PA, ''et al'' | title = Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis | journal = | volume = | issue = | pages = | year = 2007 | pmid = 17657817 | doi = 10.1002/hep.21828}}</ref>  suggesting a role of [[gluten sensitivity]] in primary biliary cirrhosis, and primary biliary cirrhosis is considerable more common in [[Gluten-sensitive enteropathy associated conditions#Diseases of the pancreas.2C gall bladder.2C bile duct|gluten sensitive enteropathy]] than the normal population.<ref name="pmid74661">{{cite journal | author = Logan RF, Ferguson A, Finlayson ND, Weir DG | title = Primary biliary cirrhosis and coeliac disease: an association? | journal = Lancet | volume = 1 | issue = 8058 | pages = 230-3 | year = 1978 | pmid = 74661 | doi = }}</ref><ref name="pmid12385447">{{cite journal | author = Volta U, Rodrigo L, Granito A, ''et al'' | title = Celiac disease in autoimmune cholestatic liver disorders | journal = Am. J. Gastroenterol. | volume = 97 | issue = 10 | pages = 2609-13 | year = 2002 | pmid = 12385447 | doi = }}</ref>
+<br>
+<div style="text-align: center;">'''Algorithm showing postulated hypothesis of pathogenesis of primary biliary cirrhosis'''<ref name="pmid19185000">{{cite journal| author=Lleo A, Selmi C, Invernizzi P, Podda M, Coppel RL, Mackay IR et al.| title=Apotopes and the biliary specificity of primary biliary cirrhosis. | journal=Hepatology | year= 2009 | volume= 49 | issue= 3 | pages= 871-9 | pmid=19185000 | doi=10.1002/hep.22736 | pmc=2665925 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19185000  }} </ref><ref name="pmid11457875">{{cite journal| author=Odin JA, Huebert RC, Casciola-Rosen L, LaRusso NF, Rosen A| title=Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. | journal=J Clin Invest | year= 2001 | volume= 108 | issue= 2 | pages= 223-32 | pmid=11457875 | doi=10.1172/JCI10716 | pmc=203018 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11457875  }} </ref><ref name="pmid8129031">{{cite journal| author=Charlotte F, L'Herminé A, Martin N, Geleyn Y, Nollet M, Gaulard P et al.| title=Immunohistochemical detection of bcl-2 protein in normal and pathological human liver. | journal=Am J Pathol | year= 1994 | volume= 144 | issue= 3 | pages= 460-5 | pmid=8129031 | doi= | pmc=1887102 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8129031  }} </ref><ref name="pmid18181218">{{cite journal| author=Shimoda S, Harada K, Niiro H, Yoshizumi T, Soejima Y, Taketomi A et al.| title=Biliary epithelial cells and primary biliary cirrhosis: the role of liver-infiltrating mononuclear cells. | journal=Hepatology | year= 2008 | volume= 47 | issue= 3 | pages= 958-65 | pmid=18181218 | doi=10.1002/hep.22102 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18181218  }} </ref></div>
+<br>
+{{Family tree/start}}
+{{Family tree | | | | | | | | | | | | A01 | | | | | | | | | | | A01=Biliary epithelial cells (BEC) }}
+{{Family tree | | | | | | | | |,|-|-|-|^|-|-|-|.| | | | | | | | }}
+{{Family tree | | | | | | | | B01 | | | | | | B02 | | | | | | | B01=Overexpression of [[Bcl-2]] in small apoptotic BEC|B02=Cell lineage specific lack of [[glutathione]]}}
+{{Family tree | | | | | | | | |!| | | | | | | |!| | | | | | | | }}
+{{Family tree | | | | | | | | |!| | | | | | | C01 | | | | | | | C01=Inhibition of PDC-E2 glutathiolation}}
+{{Family tree | | | | | | | | |`|-|-|-|v|-|-|-|'| | | | | | | | }}
+{{Family tree | | | | | | | | | | | | D01 | | | | | | | | | | | D01=Prevents loss of [[immunogenicity]] after [[apoptosis]] of BEC}}
+{{Family tree | | | | | | | | | | | | |!| | | | | | | | | | | | }}
+{{Family tree | | | | | | | | | | | | E01 | | | | | | | | | | | E01=PDC-E2 component remains intact and [[antigenic]] in [[apoptotic]] blebs of BEC}}
+{{Family tree | | | | | | | | | | | | |!| | | | | | | | | | | | }}
+{{Family tree | | | | | | | | | | | | F01 | | | | | | | | | | | F01=[[Antigenic]] PDC-E2 are engulfed by intrahepatic [[dendritic cells]]}}
+{{Family tree | | | | | | | | | | | | |!| | | | | | | | | | | | }}
+{{Family tree | | | | | | | | | | | | G01 | | | | | | | | | | | G01=[[Dendritic cells]] transfer [[antigenic]] PDC-E2 to regional [[lymph nodes]]}}
+{{Family tree | | | | | | | | | | | | |!| | | | | | | | | | | | }}
+{{Family tree | | | | | | | | | | | | H01 | | | | | | | | | | | H01=[[Antigenic]] PDC-E2 is recognized by [[MHC class I]] restricted CD8<sup>+</sup> T cells}}
+{{Family tree | | | | | | | | | | | | |!| | | | | | | | | | | | }}
+{{Family tree | | | | | | | | | | | | J01 | | | | | | | | | | | J01=Initiates [[autoimmunity]]}}
+{{Family tree | | | | | | | | | | | | |!| | | | | | | | | | | | }}
+{{Family tree | | | | | | | | | | | | K01 | | | | | | | | | | | K01=Primary biliary cirrhosis}}
+{{Family tree/end}}
-In some cases of disease, protein expression may cause an [[immune tolerance]] failure, as might be the case with [[nucleoporin 210kDa| gp210]] and [[nucleoporin 62|p62]], nuclear pore proteins. Gp210 has increased expression in the bile duct of anti-gp210 positive patients.<ref name="pmid16337775">{{cite journal | author = Nakamura M, Takii Y, Ito M, ''et al'' | title = Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis | journal = J. Autoimmun. | volume = 26 | issue = 2 | pages = 138-45 | year = 2006 | pmid = 16337775 | doi = 10.1016/j.jaut.2005.10.007}}</ref> Both proteins appear to be prognostic of liver failure relative to anti-mitochondrial antibodies.
+==Genetics==
+*Primary biliary cirrhosis may be [[familial]] and is related to factors inherited maternally.<ref name="pmid7737573">{{cite journal| author=Brind AM, Bray GP, Portmann BC, Williams R| title=Prevalence and pattern of familial disease in primary biliary cirrhosis. | journal=Gut | year= 1995 | volume= 36 | issue= 4 | pages= 615-7 | pmid=7737573 | doi= | pmc=1382507 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7737573  }} </ref>
+*Primary biliary cirrhosis tends to present at an earlier age in the second generation.
-In 2003 it was reported that an environmental gram negative alphabacterium — ''[[Novosphingobium aromaticivorans]]''<ref name=Selmi2003>{{cite journal |author=Selmi C, Balkwill DL, Invernizzi P, ''et al.'' |title=Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium |journal=Hepatology |volume=38 |issue=5 |pages=1250–7 |year=2003 |month=November |pmid=14578864 |doi=10.1053/jhep.2003.50446 }}</ref> was strongly associated with this disease. Subsequent reports appear to have confirmed this finding suggesting an aetiological role for this organism.<ref name=Mohammed2009>{{cite journal |author=Mohammed JP, Mattner J |title=Autoimmune disease triggered by infection with alphaproteobacteria |journal=Expert Rev Clin Immunol |volume=5 |issue=4 |pages=369–379 |year=2009 |month=July |pmid=20161124 |pmc=2742979 |doi=10.1586/ECI.09.23 }}</ref><ref name=Kaplan2004>{{cite journal |author=Kaplan MM |title=''Novosphingobium aromaticivorans'': a potential initiator of primary biliary cirrhosis |journal=Am. J. Gastroenterol. |volume=99 |issue=11 |pages=2147–9 |year=2004 |month=November |pmid=15554995 |doi=10.1111/j.1572-0241.2004.41121.x }}</ref><ref name=Selmi2004>{{cite journal |author=Selmi C, Gershwin ME |title=Bacteria and human autoimmunity: the case of primary biliary cirrhosis |journal=Curr Opin Rheumatol |volume=16 |issue=4 |pages=406–10 |year=2004 |month=July |pmid=15201604 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1040-8711&volume=16&issue=4&spage=406}}</ref> The mechanism appears to be a cross reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells.<ref name=Mattner2008>{{cite journal |author=Mattner J, Savage PB, Leung P, ''et al.'' |title=Liver autoimmunity triggered by microbial activation of natural killer T cells |journal=Cell Host Microbe |volume=3 |issue=5 |pages=304–15 |year=2008 |month=May |pmid=18474357 |pmc=2453520 |doi=10.1016/j.chom.2008.03.009 |url=http://linkinghub.elsevier.com/retrieve/pii/S1931-3128(08)00120-0}}</ref> The gene encoding [[cluster of differentiation 101|CD101]] may also play a role in host susceptibility to this disease.<ref name=Mohammed2003>{{cite journal |author=Mohammed JP, Fusakio ME, Rainbow DB, ''et al.'' |title=Identification of Cd101 as a susceptibility gene for ''Novosphingobium aromaticivorans''-induced liver autoimmunity |journal=J. Immunol. |volume=187 |issue=1 |pages=337–49 |year=2011 |month=July |pmid=21613619 |pmc=3134939 |doi=10.4049/jimmunol.1003525 |url=http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=21613619}}</ref>
+==Associated Conditions==
+Conditions associated with primary biliary cirrhosis include:<ref name="pmid18215315">{{cite journal| author=Kumagi T, Heathcote EJ| title=Primary biliary cirrhosis. | journal=Orphanet J Rare Dis | year= 2008 | volume= 3 | issue=  | pages= 1 | pmid=18215315 | doi=10.1186/1750-1172-3-1 | pmc=2266722 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18215315  }} </ref><ref name="pmid15208427">{{cite journal| author=Watt FE, James OF, Jones DE| title=Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study. | journal=QJM | year= 2004 | volume= 97 | issue= 7 | pages= 397-406 | pmid=15208427 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15208427  }} </ref><ref name="pmid2347546">{{cite journal| author=Tsianos EV, Hoofnagle JH, Fox PC, Alspaugh M, Jones EA, Schafer DF et al.| title=Sjögren's syndrome in patients with primary biliary cirrhosis. | journal=Hepatology | year= 1990 | volume= 11 | issue= 5 | pages= 730-4 | pmid=2347546 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2347546  }} </ref>
+*[[Addison's disease]]
+*[[Immune thrombocytopenic purpura|Autoimmune thrombocytopenic purpura]]
+*[[Celiac disease]]
+*[[CREST syndrome]]
+*[[Crohn's disease]]
+*[[Dermatomyositis]]
+*[[Diabetes mellitus type 1]]
+*[[Gallstones]]
+*[[Glomerulonephritis]]
+*[[Grave's disease]]
+*[[Hashimoto's thyroiditis]]
+*[[Lichen planus]]
+*[[Mixed connective tissue disorder]]
+*[[Myasthenia gravis]]
+*[[Pemphigoid]]
+*[[Pernicious anemia]]
+*[[Polymyositis]]
+*[[Psoriasis]]
+*[[Pulmonary fibrosis]]
+*[[Raynaud's disease]]
+*[[Rheumatoid arthritis]]
+*[[Sarcoidosis]]
+*[[Scleroderma]]
+*[[Sjogren's syndrome]]
+*[[Systemic lupus erythematosus]]
+*[[Ulcerative colitis]]
-===Genetics===
+==Gross Pathology==
-A genetic predisposition to disease has been thought important for some time, as evident by cases of PBC in family members, concordance in identical twins, and clustering of autoimmune diseases.  In 2009 a Canadian led group of investigators reported in the New England Journal of Medicine results from the first genome scan of PBC patients.<ref>{{cite journal |author=Hirschfield GM, Liu X, Xu C, ''et al.'' |title=Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants |journal=N. Engl. J. Med. |volume=360 |issue=24 |pages=2544–55 |year=2009 |month=June |pmid=19458352 |pmc=2857316 |doi=10.1056/NEJMoa0810440 |url=http://content.nejm.org/cgi/content/full/NEJMoa0810440}}</ref><ref>http://www.torontoliver.ca</ref>  This research revealed parts of the IL12 signaling cascade, particularly IL12A and IL12RB2 polymorphisms, to be important in the etiology of the disease in addition to the HLA region, suggesting future therapeutic targets.
+*On gross pathology, characteristic findings of primary biliary cirrhosis include:<ref name="pmid18215315">{{cite journal| author=Kumagi T, Heathcote EJ| title=Primary biliary cirrhosis. | journal=Orphanet J Rare Dis | year= 2008 | volume= 3 | issue=  | pages= 1 | pmid=18215315 | doi=10.1186/1750-1172-3-1 | pmc=2266722 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18215315  }} </ref>
+**[[Hepatomegaly]]
+**[[Splenomegaly]]
+**[[Cirrhosis]] (late stages)
-===Histopathology===
+==Microscopic Pathology==
-{{#ev:youtube|Jj8ozr_IttM&mode=related&search=}}
+*On microscopic histopathological analysis, asymmetric destruction of the intralobular [[bile ducts]] within [[portal triads]] is characteristic findings of primary biliary cirrhosis.
+*Primary biliary cirrhosis can be classified into four stages according to histological classification of Ludwig. According to Ludwig classification, all four stages may be present on a single [[liver biopsy]].<ref name="pmid19554543">{{cite journal| author=Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ et al.| title=Primary biliary cirrhosis. | journal=Hepatology | year= 2009 | volume= 50 | issue= 1 | pages= 291-308 | pmid=19554543 | doi=10.1002/hep.22906 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19554543  }} </ref><ref name="pmid150690">{{cite journal| author=Ludwig J, Dickson ER, McDonald GS| title=Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). | journal=Virchows Arch A Pathol Anat Histol | year= 1978 | volume= 379 | issue= 2 | pages= 103-12 | pmid=150690 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=150690  }} </ref>
+* It can also be classified into four stages according to the histological classification of P. Scheuer.<ref name="pmid6066569">{{cite journal| author=Scheuer P| title=Primary biliary cirrhosis. | journal=Proc R Soc Med | year= 1967 | volume= 60 | issue= 12 | pages= 1257-60 | pmid=6066569 | doi= | pmc=1901478 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6066569  }}</ref>
+<br>
+{|
+! colspan="3" style="background:#4479BA; color: #FFFFFF;" align="center" + | Classification of Primary biliary cirrhosis on the basis of histology
+|-
+! rowspan="2" style="background:#4479BA; color: #FFFFFF;" align="center" + |Stage
+! colspan="2" style="background:#4479BA; color: #FFFFFF;" align="center" + | Histologic appearance
+|-
+! style="background:#7d7d7d; color: #FFFFFF;" align="center" + |Ludwig classification
+! style="background:#7d7d7d; color: #FFFFFF;" align="center" + |Scheuer's classification
+|-
+| style="background:#DCDCDC;" align="center" + |Stage 1
+| style="background:#F5F5F5;" + |[[Portal]] [[inflammation]]
+| style="background:#F5F5F5;" + |Florid duct lesion or chronic non-suppurative destructive [[cholangitis]]
+|-
+| style="background:#DCDCDC;" align="center" + |Stage 2
+| style="background:#F5F5F5;" + |Extension of [[inflammation]] beyond [[portal]] tracts into surrounding [[parenchyma]] with or without ductal loss
+| style="background:#F5F5F5;" + |Proliferation of the small [[Bile duct|bile ductules]]
+|-
+| style="background:#DCDCDC;" align="center" + |Stage 3
+| style="background:#F5F5F5;" + |Presence of fibrous septa linking adjacent [[portal]] tracts
+| style="background:#F5F5F5;" + |Fibrosis or scarring
+|-
+| style="background:#DCDCDC;" align="center" + |Stage 4
+| style="background:#F5F5F5;" + |[[Cirrhosis]]
+| style="background:#F5F5F5;" + |[[Cirrhosis]]
+|}
 ==References==
 {{reflist|2}}
+{{WH}}
+{{WS}}
 [[Category:Gastroenterology]]
 [[Category:Hepatology]]
 [[Category:Disease]]
-[[Category:Needs overview]]
+[[Category:Rheumatology]]
+[[Category:Medicine]]
-{{WH}}
+[[Category:Up-To-Date]]
-{{WS}}