Przewlekła stwardniająca cholangitis – Patofizjologia i mechanizm

Przewlekła stwardniająca cholangitis
Patofizjologia i mechanizm

Przewlekła stwardniająca cholangitis (PSC) to przewlekła cholestatyczna choroba wątroby charakteryzująca się postępującym zapaleniem i włóknieniem dróg żółciowych, prowadzącym do marskości. Etiologia PSC jest wieloczynnikowa, obejmująca interakcje genetyczne (zwłaszcza związane z haplotypami HLA, np. HLA-B*08, HLA-DRB1), immunologiczne oraz środowiskowe. Genetyczne czynniki ryzyka wyjaśniają mniej niż 10% podatności, podczas gdy czynniki środowiskowe odpowiadają za ponad 50%. Patogeneza obejmuje zaburzenia zarówno wrodzonej, jak i adaptacyjnej odpowiedzi immunologicznej, z aktywacją makrofagów, komórek dendrytycznych i limfocytów T CD4+/CD8+ oraz obecnością autoprzeciwciał (ANCA u 87%, aCL u 66%, ANA u 53%). Silny związek PSC z nieswoistymi chorobami zapalnymi jelit (IBD), zwłaszcza wrzodziejącym zapaleniem jelita grubego, podkreśla rolę osi jelito-wątroba i dysbiozy jelitowej w patogenezie, z udziałem mikrobioty i toksyn bakteryjnych indukujących nieprawidłowe odpowiedzi immunologiczne cholangiocytów poprzez szlak TLR-NF-κB.

Patogeneza przewlekłej stwardniającej cholangitis

Predyspozycje genetyczne w PSC
Mechanizmy immunologiczne w patogenezie PSC
Rola mikrobioty jelitowej i oś jelito-wątroba
Toksyczność kwasów żółciowych i zaburzenia homeostazy żółci
Homing limfocytów i rekrutacja komórek zapalnych
Modele patogenetyczne PSC
Uszkodzenie cholangiocytów i rozwój włóknienia
Model wieloetapowej karcynogenezy w PSC

Podsumowanie aktualnej wiedzy na temat patogenezy PSC

Kolejne rozdziały

Patogeneza przewlekłej stwardniającej cholangitis

Przewlekła stwardniająca cholangitis (PSC) to przewlekła cholestatyczna choroba wątroby charakteryzująca się postępującym zapaleniem i włóknieniem wewnątrz- i/lub zewnątrzwątrobowych dróg żółciowych, prowadzącym ostatecznie do marskości wątroby. Mimo wielu lat badań, dokładna etiologia i patogeneza PSC pozostaje nie w pełni wyjaśniona, a obecnie uważa się, że choroba rozwija się w wyniku złożonej interakcji czynników genetycznych, immunologicznych i środowiskowych.¹²

Predyspozycje genetyczne w PSC

Dowody wskazujące na genetyczną predyspozycję do PSC pochodzą z obserwacji rodzinnego i geograficznego występowania choroby, z wyższą częstością w krajach północnych (np. Norwegia, Szwecja) w porównaniu z południową Europą i Azją.³ Badania genetyczne wykazały, że członkowie najbliższej rodziny pacjentów z PSC mają zwiększone ryzyko rozwoju tej choroby (nawet 11-krotnie).⁴

Szczególnie istotne znaczenie w podatności genetycznej na PSC mają geny kompleksu głównego układu zgodności tkankowej (HLA). Silne związki z haplotypami HLA, w tym HLA klasy I (HLA-B*08), klasy II (allele HLA-DRB1) i klasy III (locus w pobliżu NOTCH4), są najsilniejszym genetycznym czynnikiem ryzyka PSC.⁵⁶ Badania asocjacji całego genomu (GWAS) zidentyfikowały ponad 20 genów podatności na PSC, przy czym większość z nich lokalizuje się w obrębie kompleksu HLA.⁷⁸

Poza genami HLA, zidentyfikowano również geny związane z funkcją limfocytów T, homeostazą kwasów żółciowych oraz innymi procesami zapalnymi. Jednakże, odkrycia genetyczne w PSC wyjaśniają mniej niż 10% podatności na chorobę, a czynniki środowiskowe szacuje się na ponad 50% niewyjaśnionej frakcji.⁹

Mechanizmy immunologiczne w patogenezie PSC

Patogeneza PSC obejmuje zaburzenia zarówno wrodzonej, jak i nabytej odpowiedzi immunologicznej.¹⁰ Odpowiedź wrodzona jest uważana za pierwotne zdarzenie inicjujące w patogenezie PSC.¹¹¹² W konsekwencji, komórki zapalne, takie jak makrofagi, komórki dendrytyczne i komórki NK, są aktywowane przez receptory rozpoznające wzorce molekularne, wydzielają cytokiny i nasilają reakcję zapalną poprzez aktywację komórek NK przez IL-12 oraz rekrutację limfocytów za pośrednictwem TNF-α, IL-1 i CXCL8.¹³

Silne związki z HLA znalezione w badaniach genetycznych sugerują, że odpowiedzi adaptacyjne układu immunologicznego również odgrywają istotną rolę. Cząsteczki HLA klasy I i II prezentują potencjalnie antygenne peptydy, pochodzące z wewnątrzkomórkowych i zewnątrzkomórkowych źródeł, receptorowi TCR na komórkach T CD8+ i CD4+. Antygeny pochodzące z jelit prezentowane przez warianty HLA związane z PSC dla receptora komórek T są potencjalnymi czynnikami wyzwalającymi te odpowiedzi.¹⁴

U pacjentów z PSC obserwuje się zwiększony poziom autoprzeciwciał, w tym przeciwciał przeciw cytoplazmie neutrofilów (ANCA) u 87%, przeciwciał antykardiolipinowych (aCL) u 66% i przeciwciał przeciwjądrowych (ANA) u 53% pacjentów.¹⁵ Jednakże PSC nie jest klasyczną chorobą autoimmunologiczną, gdyż nie wykazuje typowych cech, takich jak przewaga u kobiet, obecność patogennych autoprzeciwciał i odpowiedź na leki immunosupresyjne.¹⁶

Rola mikrobioty jelitowej i oś jelito-wątroba

Silny związek PSC z nieswoistymi chorobami zapalnymi jelit (IBD), szczególnie z wrzodziejącym zapaleniem jelita grubego (UC), które występuje u większości pacjentów z PSC, sugeruje istotną rolę osi jelito-wątroba w patogenezie tej choroby.¹⁷¹⁸ Wiele czynników wspiera udział mikrobioty jelitowej w patogenezie PSC, w tym dane z badań GWAS identyfikujące warianty genetyczne w PSC związane z UC (takie jak kodujące GPR35) lub wpływające na bakteryjny skład żółci (takie jak kodujące FUT2), obecność produktów bakteryjnych w eksplantach wątroby pacjentów z PSC, wzrost bakterii i grzybów z hodowli żółci pobranych podczas pierwszego ERCP oraz zwiększona odpowiedź komórek T na czynniki mikrobiologiczne.¹⁹

Badania in vitro wykazały, że komórki nabłonka dróg żółciowych izolowane od pacjentów z PSC mają nieprawidłowe odpowiedzi immunologiczne TLR-NF-κB na endotoksyny jelitowe ze zwiększoną produkcją prozapalnych cytokin, takich jak IL-8 i TNF-α, co sugeruje, że cytokiny prozapalne i endotoksyny indukują nieprawidłowe odpowiedzi odpornościowe w aktywowanych cholangiocytach u pacjentów z PSC.²⁰

U pacjentów z PSC obserwuje się ogólne zmniejszenie różnorodności bakteryjnej i zmiany w abundancji niektórych bakterii w mikrobiota jelit w porównaniu ze stanem zdrowym. Przypuszcza się, że dysbioza jelitowa w PSC może być wtórnym zdarzeniem w chorobie, ale mikrobiota jelitowa odgrywa również aktywną rolę w progresji choroby poprzez dysfunkcję bariery jelitowej i translokację zjadliwych bakterii i toksyn.²¹²²

W modelach doświadczalnych wykazano, że Klebsiella pneumoniae może indukować uszkodzenia dróg żółciowych wtórnie do indukcji wątrobowej odpowiedzi immunologicznej zależnej od komórek Th17.²³ Mikrobiota jelitowa u pacjentów z PSC funkcjonalnie różni się od mikrobioty u zdrowych osób, wykazując obniżony poziom witaminy B6 i aminokwasów o rozgałęzionych łańcuchach.²⁴

Toksyczność kwasów żółciowych i zaburzenia homeostazy żółci

Stan zapalny i włóknienie prowadzą do cholestazy i uszkodzenia miąższu wątroby. U pacjentów z PSC-IBD zaobserwowano charakterystyczny profil kwasów żółciowych z bezpośrednim toksycznym wpływem na cholangiocyty, co przyczynia się do progresji choroby.²⁵ Pierwotne lub wtórne zaburzenia homeostazy żółci jako część procesów chorobowych w drogach żółciowych lub okrężnicy, lub deficyty mechanizmów ochronnych lub kompensacyjnych, takie jak tak zwany parasol wodorowęglanowy, zostały również zaangażowane w patogenezę PSC.²⁶

Lokalizacja zapalenia wątroby w drzewie żółciowym w PSC sugeruje, że zaburzenia kwasów żółciowych lub kolonizacja mikrobiologiczna mogą przyczyniać się do patofizjologii PSC. Potwierdza to identyfikacja loci podatności innych niż HLA u pacjentów z PSC, związanych z regulacją wydzielania kwasów żółciowych i wodorowęglanów.²⁷ Cholangiocyty wykazują aktywowany fenotyp w PSC, co może dalej wyzwalać odpowiedź immunologiczną poprzez interakcje z komórkami gwiaździstymi wątroby i/lub miofibroblastami wrotnym, promując rozwój zwłóknienia okołoprzewodowego i ostatecznie marskości.²⁸

Homing limfocytów i rekrutacja komórek zapalnych

Interesujące jest, że ekspresja MAdCAM-1 (mucosal vascular addressin cell adhesion molecule 1) i białka adhezyjnego naczyń 1 (VAP-1) wraz z wydzielaniem CCL25 jest wspólna dla układów pokarmowego i wątrobowego u pacjentów z PSC, co umożliwia aktywowanym komórkom T wiązanie się zarówno z błoną śluzową jelita, jak i śródbłonkiem wątroby.²⁹

Teoria rekrutacji limfocytów jelitowych do wątroby sugeruje, że limfocyty aktywowane w jelicie u pacjentów z IBD różnicują się w komórki efektorowe zdolne do wiązania się zarówno z śródbłonkiem wątrobowym, jak i śluzówkowym.³⁰ Po ekspansji klonalnej, aktywowane komórki T mogą migrować zarówno do wątroby, jak i jelit z powodu nakładającej się ekspresji w jelicie i wątrobie istotnych składników kierujących limfocyty, w tym MAdCAM-1, VCAM-1 (vascular cell adhesion molecule 1), integryny α4β7, wraz z wydzielaniem chemokiny CCL25, przyczyniając się do patogenezy PSC.³¹

W wątrobie te zrekrutowane limfocyty zostały zaangażowane w zapalenie dróg żółciowych prowadzące do apoptozy i martwicy cholangiocytów, a ostatecznie do włóknienia.³²³³

Modele patogenetyczne PSC

Zaproponowano kilka modeli roboczych w celu wyjaśnienia wielu osobliwych cech PSC, a mianowicie silnego związku z IBD, obserwacji, że PSC może rozwijać się po całkowitej kolektomii oraz że aktywność choroby wątroby w PSC nie koreluje z aktywnością choroby jelitowej IBD.³⁴

Model Vierlinga – zaproponował, że immunopatogeneza PSC obejmuje wiele etapów, począwszy od aktywacji cholangiocyta przez patogen bakteryjny, który przemieszcza się do wątroby z jelit.³⁵
Teoria homingu limfocytów śluzówkowych – sugeruje, że limfocyty są aktywowane w jelicie u pacjentów z IBD, a następnie nieprawidłowo rekrutowane do miejsc pozajelitowych.³⁶
Teoria Fickerta – porównuje patogenezę PSC do miażdżycy.³⁷
Hipoteza „nieszczelnego jelita” – z powodu związku IBD z PSC, zaproponowano hipotezę nieszczelnego jelita. Według niej antygeny bakteryjne lub toksyny przenikają przez zwiększoną przepuszczalność jelita do krążenia wrotnego, wywołując odpowiedź zapalną w wątrobie.³⁸³⁹

Uszkodzenie cholangiocytów i rozwój włóknienia

Komórki nabłonka dróg żółciowych (BECs, cholangiocyty) odgrywają aktywną rolę w propagowaniu odpowiedzi prozapalnej i prowłóknieniowej.⁴⁰ Cholangiocyty są wyjątkowo wrażliwe na ogólnoustrojowe warunki immunologiczne i mają aktywny udział w kształtowaniu odpowiedzi prozapalnej i prowłóknieniowej.⁴¹

Biorąc pod uwagę silny związek między PSC a IBD, cholangiocyty w PSC mogą być narażone na zwiększoną ilość LPS lub innych antygenów uwalnianych z zapalnego jelita, co następnie wyzwala sygnalizację pośredniczoną przez TLR.⁴² Zapalenie jelita powoduje zwiększoną przepuszczalność dla LPS i może powodować uszkodzenie dróg żółciowych u genetycznie podatnego gospodarza poprzez szlak LPS-TLR4-NF-κB.⁴³

W przewlekłym zapaleniu cholangiocyty wykazują wysoką zdolność proliferacyjną jako odpowiedź adaptacyjną w celu zapobiegania duktopenii i mogą również działać jako fakultatywne komórki macierzyste wątroby w przypadku znacznego uszkodzenia wątroby.⁴⁴

Najbardziej klasyczne zmiany histopatologiczne PSC obejmują duże przewody żółciowe otoczone koncentrycznym włóknieniem, nazywanym również włóknieniem o układzie „cebulkowym” (onion skin fibrosis).⁴⁵ W miarę postępu choroby dochodzi do utraty przewodów żółciowych (duktopenia), a zmiany włóknisto-obliteracyjne lub blizny zastępują przewody żółciowe w przestrzeniach wrotnych. Uszkodzenie przewodów żółciowych może być obecne, jednak jego nasilenie zależy od czasu trwania choroby.⁴⁶

Model wieloetapowej karcynogenezy w PSC

Najbardziej wspieranym modelem karcynogenezy dróg żółciowych jest model „karcynogenezy wieloetapowej”. Obecność przewlekłego zapalenia prowadzi do sekwencyjnej progresji od uszkodzonego prawidłowego nabłonka dróg żółciowych do dysplazji małego stopnia (LGD), dysplazji dużego stopnia (HGD), a ostatecznie inwazyjnego raka.⁴⁷

W eksplantowanej wątrobie pacjentów, którzy rozwinęli PSC-CCA (cholangiocarcinoma związany z PSC), obserwowano wyższą częstość metaplazji i dysplazji niż w samym PSC, co sugeruje, że te zmiany histologiczne mogą poprzedzać rozwój CCA.⁴⁸ Metaplazja jelitowa stanowi istotny czynnik predykcyjny zarówno dysplazji, jak i CCA, potwierdzając istnienie wieloetapowego procesu transformacji nowotworowej i częściowo różnicując patogenezę PSC-CCA od samego CCA.⁴⁹

Podsumowanie aktualnej wiedzy na temat patogenezy PSC

Patogeneza PSC jest złożona i wieloczynnikowa, obejmująca interakcje między predyspozycją genetyczną, odpowiedzią immunologiczną, mikrobiotą jelitową, toksycznością kwasów żółciowych oraz zaburzeniami bariery śluzówkowej dróg żółciowych.⁵⁰⁵¹

Najbardziej prawdopodobna koncepcja patogenezy PSC obejmuje ekspozycję genetycznie predysponowanych osób na antygen środowiskowy, który następnie wywołuje nieprawidłową odpowiedź immunologiczną, prowadzącą do rozwoju choroby.⁵² Genetyczne lub chemicznie modyfikowane składniki żółci mogą indukować stwardniające zapalenie dróg żółciowych i włóknienie wątroby w wielu modelach zwierzęcych (tzw. „koncepcja toksycznej żółci”).⁵³

Potencjalna rola uszkodzenia naczyń z niedokrwieniem komórek nabłonka przewodów żółciowych w rozwoju stwardniającego zapalenia dróg żółciowych jest wspierana przez modele zwierzęce uszkodzenia komórek śródbłonka wykazujące bliskie podobieństwa morfologiczne z ludzkim PSC.⁵⁴

Pomimo znacznego postępu w zrozumieniu patogenezy PSC, nadal istnieją krytyczne luki w wiedzy dotyczące pierwotnych i wtórnych procesów chorobowych. Wyjaśnienie tych mechanizmów jest kluczowe dla opracowania skutecznych terapii celowanych, które mogłyby zmienić naturalny przebieg tej postępującej choroby wątroby.⁵⁵⁵⁶

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Materiały źródłowe

#1 Pathogenesis of primary sclerosing cholangitis
https://pmc.ncbi.nlm.nih.gov/articles/PMC3236286/
Primary sclerosing cholangitis (PSC) represents a chronic cholestatic liver disease with fibroobliterative sclerosis of intra- and/or extrahepatic bile ducts, eventually leading to biliary cirrhosis. […] The association with human leukocyte antigen (HLA) and non-HLA haplotypes and the presence of autoantibodies in sera of PSC patients support a crucial role for immune-mediated mechanisms in the initiation and progression of PSC. […] Genetically or chemically modified bile composition was shown to induce sclerosing cholangitis and liver fibrosis in a number of animal models („toxic bile concept”). […] The potential role of vascular injury with ischemia of bile duct epithelium cells in the development of sclerosing cholangitis is supported by animal models of endothelial cell injury showing close morphological similarities with human PSC.
#2 Primary Sclerosing Cholangitis – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK537181/
Primary sclerosing cholangitis (PSC) is a chronic and progressive cholestatic liver disorder of unknown etiology. Inflammation, fibrosis, and stricturing of intrahepatic or extrahepatic biliary ducts characterize PSC. PSC is usually a progressive disorder that leads to complications of cholestasis and liver failure. Median survival from the time of diagnosis to death without liver transplantation is around 10 years. […] PSC is characterized by inflammation, fibrosis, and cholestasis. Hereditary and environmental factors play a role in the pathogenesis of PSC. Healthcare researchers hypothesize that after exposure to an unidentified environmental source, persistent injury of the cells lining the bile ducts (cholangiocytes) occurs via several genetically predisposed pathways. […] A large cohort genome-wide association study showed a strong association with specific human leukocyte antigens (HLA). PSC is strongly associated with HLA class 1, 2, and 3 regions (ie, HLA-B*08, HLA-DRB1 alleles, and a locus near NOTCH4, respectively). Inflammation and fibrosis lead to cholestasis and parenchymal injury. Biliary obstruction might facilitate cholangitis. Biliary scarring leads to portal hypertension, which causes venous compression in the portal triads. PSC is a premalignant disease, as 10% to 20% of patients with PSC develop cholangiocarcinoma. PSC-induced cholangiocarcinoma is thought to be inflammation-induced cancer contributed by the toxic environment of bile, which acts as a cofactor in accelerating carcinogenesis. Genetic and immune factors may play an important role. […] The secretion of chemokines and cytokines by innate immune cells and inflammatory and fibrotic response to toxic bile leaking between inured cholangiocytes leads to periductal fibrosis.
#3 Pathogenesis of primary sclerosing cholangitis
https://pmc.ncbi.nlm.nih.gov/articles/PMC3236286/
Evidence supporting a genetic predisposition for PSC is derived from an obvious familial and geographic clustering with high prevalence in Northern countries (e.g. Norway, Sweden) compared to Southern Europe and Asia. […] Based on its associations with HLA haplotypes, autoimmune diseases and the presence of inflammatory bowel disease (IBD), especially ulcerative colitis (UC) in the majority of PSC patients, immunopathogenetic mechanisms have been implicated in PSC pathogenesis. […] Although the mechanistic links between PSC and IBD are still not satisfactorily explained, this association of PSC suggests a common pathogenetic agent or common inflammatory pathway in the pathogenesis of both diseases. […] The hepatic innate immune response has been considered to be a primary inciting event in the pathogenesis of PSC.
#4 Primary sclerosing cholangitis – Rabiee – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/6491/html
The pathogenesis of PSC is not fully understood but appears to be multifactorial and several mechanistic theories have been proposed. Cholangiocyte injury appears to result from environmental exposure and an abnormal cholangiocyte immune response leading to clinical disease in genetically susceptible individuals. Little is known about the role of the environmental risks including the influence of colonic toxins, gut microbiota, portal bacteria, or viral infections. […] The role of genetic factors in the etiology of PSC is underscored by the finding that first-degree relatives of patients with PSC have an increased risk of PSC (up to 11-fold). Genetic susceptibility factors for PSC may overlap with UC as first-degree relatives of patients with PSC without IBD are also at an increased risk of UC (8-fold). Through the application of genome-wide association studies, greater than 20 susceptibility genes for PSC have been established, with the human leukocyte antigen (HLA) complex on chromosome six representing the strongest finding by several orders of magnitude. The overall genetic architecture of PSC appears to share features with both autoimmune diseases and IBD. Strong HLA gene associations, along with several susceptibility genes that are critically involved in T-cell function, support the involvement of adaptive immune responses in development of disease, and support the long-standing notion of PSC as an autoimmune disease. Nonetheless, genetic findings in PSC so far explain less than 10% of disease liability, and environmental risk factors are estimated to account for greater than 50% of the unexplained fraction.
#5 Primary Sclerosing Cholangitis – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK537181/
Primary sclerosing cholangitis (PSC) is a chronic and progressive cholestatic liver disorder of unknown etiology. Inflammation, fibrosis, and stricturing of intrahepatic or extrahepatic biliary ducts characterize PSC. PSC is usually a progressive disorder that leads to complications of cholestasis and liver failure. Median survival from the time of diagnosis to death without liver transplantation is around 10 years. […] PSC is characterized by inflammation, fibrosis, and cholestasis. Hereditary and environmental factors play a role in the pathogenesis of PSC. Healthcare researchers hypothesize that after exposure to an unidentified environmental source, persistent injury of the cells lining the bile ducts (cholangiocytes) occurs via several genetically predisposed pathways. […] A large cohort genome-wide association study showed a strong association with specific human leukocyte antigens (HLA). PSC is strongly associated with HLA class 1, 2, and 3 regions (ie, HLA-B*08, HLA-DRB1 alleles, and a locus near NOTCH4, respectively). Inflammation and fibrosis lead to cholestasis and parenchymal injury. Biliary obstruction might facilitate cholangitis. Biliary scarring leads to portal hypertension, which causes venous compression in the portal triads. PSC is a premalignant disease, as 10% to 20% of patients with PSC develop cholangiocarcinoma. PSC-induced cholangiocarcinoma is thought to be inflammation-induced cancer contributed by the toxic environment of bile, which acts as a cofactor in accelerating carcinogenesis. Genetic and immune factors may play an important role. […] The secretion of chemokines and cytokines by innate immune cells and inflammatory and fibrotic response to toxic bile leaking between inured cholangiocytes leads to periductal fibrosis.
#6 Primary Sclerosing Cholangitis: Background, Etiopathophysiology, Epidemiology
https://emedicine.medscape.com/article/931355-overview
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by a progressive course of cholestasis with inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. The underlying cause of the inflammation is believed to be autoimmune. […] An autoimmune mechanism is suggested, because approximately 70% of patients with PSC have inflammatory bowel disease (IBD). However, only approximately 4% of patients with IBD have or develop PSC. A marked increase in serum autoantibody levels occurs in patients with PSC as well, with antineutrophil cytoplasmic antibodies (ANCA) in 87%, anticardiolipin (aCL) antibodies in 66%, and antinuclear antibodies (ANA) in 53%. It has been reported that PSC and IBD have overlapping yet distinct genetic architectures. […] In the biliary ducts, an inflammatory response to chronic or recurrent bacterial infection in the portal circulation and from exposure to toxic bile acids has been postulated. A genetic predisposition has been suggested because of an increased prevalence of HLA-B8, HLA-DR3, and HLA-Drw52a. Genome-wide association studies (GWAS) performed in PSC have identified about 20 genes that are significantly associated with PSC, most of which localize within the human leukocyte antigen (HLA) complex. […] Therefore, the most plausible concept of the pathogenesis of PSC involves the exposure of genetically predisposed individuals to an environmental antigen that subsequently elicits an aberrant immune response, leading to development of the disease.
#7 Primary sclerosing cholangitis – Rabiee – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/6491/html
The pathogenesis of PSC is not fully understood but appears to be multifactorial and several mechanistic theories have been proposed. Cholangiocyte injury appears to result from environmental exposure and an abnormal cholangiocyte immune response leading to clinical disease in genetically susceptible individuals. Little is known about the role of the environmental risks including the influence of colonic toxins, gut microbiota, portal bacteria, or viral infections. […] The role of genetic factors in the etiology of PSC is underscored by the finding that first-degree relatives of patients with PSC have an increased risk of PSC (up to 11-fold). Genetic susceptibility factors for PSC may overlap with UC as first-degree relatives of patients with PSC without IBD are also at an increased risk of UC (8-fold). Through the application of genome-wide association studies, greater than 20 susceptibility genes for PSC have been established, with the human leukocyte antigen (HLA) complex on chromosome six representing the strongest finding by several orders of magnitude. The overall genetic architecture of PSC appears to share features with both autoimmune diseases and IBD. Strong HLA gene associations, along with several susceptibility genes that are critically involved in T-cell function, support the involvement of adaptive immune responses in development of disease, and support the long-standing notion of PSC as an autoimmune disease. Nonetheless, genetic findings in PSC so far explain less than 10% of disease liability, and environmental risk factors are estimated to account for greater than 50% of the unexplained fraction.
#8 Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gutâliver axis | Experimental & Molecular Medicine
https://www.nature.com/articles/s12276-023-01042-9
In summary, the genetic predisposition for PSC seems to involve HLA genes and genes related to T cells, BA homeostasis, and other inflammatory conditions. […] The pathogenesis of PSC-IBD involves the perturbation of both innate and adaptive immunity. […] Cholangiocytes are exceptionally sensitive to systemic immune conditions and have an active role in cultivating the proinflammatory and profibrotic response. […] Given the strong link between PSC and IBD, cholangiocytes in PSC may be exposed to an increased amount of LPS or other antigens released from the inflamed gut, which then triggers TLR-mediated signaling. […] Thus, intestinal inflammation causes increased leakage of LPS and may cause biliary damage in a genetically susceptible host through the LPSTLR4NF-B axis pathway. […] The strong linkage between PSC and IBD implies hepatic inflammation originating in the intestine.
#9 Primary sclerosing cholangitis – Rabiee – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/6491/html
The pathogenesis of PSC is not fully understood but appears to be multifactorial and several mechanistic theories have been proposed. Cholangiocyte injury appears to result from environmental exposure and an abnormal cholangiocyte immune response leading to clinical disease in genetically susceptible individuals. Little is known about the role of the environmental risks including the influence of colonic toxins, gut microbiota, portal bacteria, or viral infections. […] The role of genetic factors in the etiology of PSC is underscored by the finding that first-degree relatives of patients with PSC have an increased risk of PSC (up to 11-fold). Genetic susceptibility factors for PSC may overlap with UC as first-degree relatives of patients with PSC without IBD are also at an increased risk of UC (8-fold). Through the application of genome-wide association studies, greater than 20 susceptibility genes for PSC have been established, with the human leukocyte antigen (HLA) complex on chromosome six representing the strongest finding by several orders of magnitude. The overall genetic architecture of PSC appears to share features with both autoimmune diseases and IBD. Strong HLA gene associations, along with several susceptibility genes that are critically involved in T-cell function, support the involvement of adaptive immune responses in development of disease, and support the long-standing notion of PSC as an autoimmune disease. Nonetheless, genetic findings in PSC so far explain less than 10% of disease liability, and environmental risk factors are estimated to account for greater than 50% of the unexplained fraction.
#10 Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gutâliver axis | Experimental & Molecular Medicine
https://www.nature.com/articles/s12276-023-01042-9
In summary, the genetic predisposition for PSC seems to involve HLA genes and genes related to T cells, BA homeostasis, and other inflammatory conditions. […] The pathogenesis of PSC-IBD involves the perturbation of both innate and adaptive immunity. […] Cholangiocytes are exceptionally sensitive to systemic immune conditions and have an active role in cultivating the proinflammatory and profibrotic response. […] Given the strong link between PSC and IBD, cholangiocytes in PSC may be exposed to an increased amount of LPS or other antigens released from the inflamed gut, which then triggers TLR-mediated signaling. […] Thus, intestinal inflammation causes increased leakage of LPS and may cause biliary damage in a genetically susceptible host through the LPSTLR4NF-B axis pathway. […] The strong linkage between PSC and IBD implies hepatic inflammation originating in the intestine.
#11 Pathogenesis of primary sclerosing cholangitis
https://pmc.ncbi.nlm.nih.gov/articles/PMC3236286/
Evidence supporting a genetic predisposition for PSC is derived from an obvious familial and geographic clustering with high prevalence in Northern countries (e.g. Norway, Sweden) compared to Southern Europe and Asia. […] Based on its associations with HLA haplotypes, autoimmune diseases and the presence of inflammatory bowel disease (IBD), especially ulcerative colitis (UC) in the majority of PSC patients, immunopathogenetic mechanisms have been implicated in PSC pathogenesis. […] Although the mechanistic links between PSC and IBD are still not satisfactorily explained, this association of PSC suggests a common pathogenetic agent or common inflammatory pathway in the pathogenesis of both diseases. […] The hepatic innate immune response has been considered to be a primary inciting event in the pathogenesis of PSC.
#12
https://link.springer.com/article/10.1007/s00281-009-0154-7
The activation of the innate immune system as a primary inciting event of PSC has been proposed by several investigators. According to this theory, PSC is triggered by bacteria or more likely, pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), lipoteichoic acid, peptidoglycans, and unmethylated bacterial dinucleotide motifs that enter the portal circulation through an inflamed permeable intestine. […] Similar to the intestinal mucosa, the biliary mucosa expresses multiple TLRs and their expression has been shown to be induced in a variety of liver diseases. […] The targets of these anti-BEC antibodies remain unknown and other evidence that innate immune responses are dysregulated in PSC is largely circumstantial.
#13 Pathogenesis of primary sclerosing cholangitis
https://pmc.ncbi.nlm.nih.gov/articles/PMC3236286/
Consequently, inflammatory cells, such as macrophages, dentritic cells (DCs), and NK cells are activated through pattern recognition receptors, secrete cytokines and perpetuate inflammatory reaction by activation of NK cells through IL-12 and recruitment of lymphocytes via TNF-, IL-1 and CXCL8. […] Biliary epithelial cells (BECs) have an active role in propagating the proinflammatory and profibrotic response. […] Taken together, the general problem of defining cell response in PSC can be attributed to the difficult detection of early PSC lesions in representative tissues.
#14 Primary sclerosing cholangitis – Rabiee – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/6491/html
The strong HLA associations found in genetic studies suggest that adaptive immune responses are involved. The HLA class I and class II molecules present potentially antigenic peptides, derived from intracellular and extracellular sources, respectively, to the T cell receptor on CD8 and CD4 positive T cells. Gut derived antigens presented by PSC-associated HLA variants to the T cell receptor are potential triggers of these responses, and activated T cells may migrate to both the liver and gut following clonal expansion because of the overlapping expression in the gut and the liver of relevant lymphocyte homing components including mucosal vascular address in cell adhesion molecule 1 (MadCAM-1) and vascular cell adhesion molecule 1 (VCAM-1), 47 integrin, along with Chemokine C-C motif ligand 25 (CCL25) secretion, and contribute to the pathogenesis of PSC. In the liver, these recruited lymphocytes have been implicated in biliary inflammation leading to apoptosis and necrosis of cholangiocytes, and eventually fibrosis.
#15 Primary Sclerosing Cholangitis: Background, Etiopathophysiology, Epidemiology
https://emedicine.medscape.com/article/931355-overview
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by a progressive course of cholestasis with inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. The underlying cause of the inflammation is believed to be autoimmune. […] An autoimmune mechanism is suggested, because approximately 70% of patients with PSC have inflammatory bowel disease (IBD). However, only approximately 4% of patients with IBD have or develop PSC. A marked increase in serum autoantibody levels occurs in patients with PSC as well, with antineutrophil cytoplasmic antibodies (ANCA) in 87%, anticardiolipin (aCL) antibodies in 66%, and antinuclear antibodies (ANA) in 53%. It has been reported that PSC and IBD have overlapping yet distinct genetic architectures. […] In the biliary ducts, an inflammatory response to chronic or recurrent bacterial infection in the portal circulation and from exposure to toxic bile acids has been postulated. A genetic predisposition has been suggested because of an increased prevalence of HLA-B8, HLA-DR3, and HLA-Drw52a. Genome-wide association studies (GWAS) performed in PSC have identified about 20 genes that are significantly associated with PSC, most of which localize within the human leukocyte antigen (HLA) complex. […] Therefore, the most plausible concept of the pathogenesis of PSC involves the exposure of genetically predisposed individuals to an environmental antigen that subsequently elicits an aberrant immune response, leading to development of the disease.
#16 Pathogenesis and clinical spectrum of primary sclerosing cholangitis
https://www.wjgnet.com/1007-9327/full/v23/i14/2459.htm
Primary sclerosing cholangitis (PSC) is a disease of the biliary tract, which has been documented in the literature since 1867. […] The exact pathogenesis of PSC is not well understood at present, however, is likely a combination of a genetic predisposition with alteration of the molecular structure of the gut. […] The pathogenic mechanisms of PSC remain incompletely understood. Much like other autoimmune diseases, it has been theorized that the development of PSC is more likely to occur in a genetically susceptible individual after exposure to a trigger. PSC is the result of a complex immune-mediated response rather than a true autoimmune disease as it does not present with classic autoimmune features: female predominance, pathogenic autoantibodies, and response to immunosuppressive medications.
#17 Pathogenesis of primary sclerosing cholangitis
https://pmc.ncbi.nlm.nih.gov/articles/PMC3236286/
Evidence supporting a genetic predisposition for PSC is derived from an obvious familial and geographic clustering with high prevalence in Northern countries (e.g. Norway, Sweden) compared to Southern Europe and Asia. […] Based on its associations with HLA haplotypes, autoimmune diseases and the presence of inflammatory bowel disease (IBD), especially ulcerative colitis (UC) in the majority of PSC patients, immunopathogenetic mechanisms have been implicated in PSC pathogenesis. […] Although the mechanistic links between PSC and IBD are still not satisfactorily explained, this association of PSC suggests a common pathogenetic agent or common inflammatory pathway in the pathogenesis of both diseases. […] The hepatic innate immune response has been considered to be a primary inciting event in the pathogenesis of PSC.
#18 Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gutâliver axis | Experimental & Molecular Medicine
https://www.nature.com/articles/s12276-023-01042-9
The close relationship between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) provides a good opportunity to comprehend the gutliver axis. […] Understanding the pathogenesis of PSC-IBD helps to develop novel and effective therapeutic agents. […] While the pathogenesis of PSC-IBD remains unknown, recent studies suggest that multiple factors, including genetic susceptibility, the immune-mediated pathway, alterations in BAs, and gut dysbiosis, may contribute to the pathogenesis of PSC-IBD. […] Furthermore, the close link between IBD and PSC likely represents an important example of how dysfunction of the gutliver axis can lead to clinical disease. […] In the liver, genetic predisposition and immune-mediated pathways are primarily involved in the pathogenesis of PSC with impaired bile acid (BA) homeostasis.
#19 Primary sclerosing cholangitis – Rabiee – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/6491/html
Several factors support the involvement of the gut microbiota in the pathogenesis of PSC, including the long described association of PSC with IBD, genome-wide association study data identifying genetic variants in PSC that are associated with UC (such as those encoding GPR35) or influence biliary bacterial composition (such as those encoding FUT2), the presence of bacterial products in the liver explants of patients with PSC, growth of bacteria and fungi from bile cultures acquired at time of first ERCP and increased T-cell response to microbial agents. Conversely, in vitro data have shown that biliary epithelial cells isolated from patients with PSC have aberrant TLR-nuclear factor-B (NF-B) immune responses to intestinal endotoxins with increased production of pro-inflammatory cytokines, such as IL-8 and TNF-, suggesting that pro-inflammatory cytokines and endotoxins induce inappropriate innate immune responses in activated cholangiocytes in patients with PSC. Additionally, an overall reduction in bacterial diversity and altered abundance of certain bacteria in gut microbiota is observed in patients with PSC compared with the healthy state, but the mechanisms by which this alteration in gut microbial community results in disease remain unclear.
#20 Primary sclerosing cholangitis – Rabiee – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/6491/html
Several factors support the involvement of the gut microbiota in the pathogenesis of PSC, including the long described association of PSC with IBD, genome-wide association study data identifying genetic variants in PSC that are associated with UC (such as those encoding GPR35) or influence biliary bacterial composition (such as those encoding FUT2), the presence of bacterial products in the liver explants of patients with PSC, growth of bacteria and fungi from bile cultures acquired at time of first ERCP and increased T-cell response to microbial agents. Conversely, in vitro data have shown that biliary epithelial cells isolated from patients with PSC have aberrant TLR-nuclear factor-B (NF-B) immune responses to intestinal endotoxins with increased production of pro-inflammatory cytokines, such as IL-8 and TNF-, suggesting that pro-inflammatory cytokines and endotoxins induce inappropriate innate immune responses in activated cholangiocytes in patients with PSC. Additionally, an overall reduction in bacterial diversity and altered abundance of certain bacteria in gut microbiota is observed in patients with PSC compared with the healthy state, but the mechanisms by which this alteration in gut microbial community results in disease remain unclear.
#21 Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gutâliver axis | Experimental & Molecular Medicine
https://www.nature.com/articles/s12276-023-01042-9
Dysbiosis in IBD patients is evident in that a decrease in the bacterial diversity and an increase in the composition of certain virulent bacteria could exaggerate the immune response. […] The gut microbiota in PSC patients has been found to be functionally different than that in healthy controls, exhibiting a decreased level of vitamin B6 and branched-chain amino acids. […] Therefore, K. pneumoniae may induce hepatobiliary tract damage secondary to inducing the hepatic Th17 cell-mediated immune response. […] Alterations in the gut microbiota in PSC might be a secondary event in the disease, whereas the gut microbiota is also involved and has an active part in disease progression through aspects involving gut barrier dysfunction and the translocation of virulent bacteria and toxins.
#22
https://xiahepublishing.com/2310-8819/JCTH-2022-00068S
Studies of the stool and ileocolonic microbiota in PSC by RNA 16S analysis have consistently demonstrated reduced diversity and dominance of certain bacterial communities in PSC patients compared with healthy controls and patients with IBD alone, with similar differences noted in bile and upper gastrointestinal tract microbiota studies. […] The gut microbiota dysbiosis in PSC ties in with the hypothesis of gut-liver inflammation due to activation of vascular adhesion protein-1 (VAP1) by copper amine oxidase proteins. These proteins are produced by specific bacteria such as Veilonella, that are identified in the colonic tissue of patients with PSC and IBD which acts as substrates for VAP1 that mediates lymphocyte trafficking.
#23 Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gutâliver axis | Experimental & Molecular Medicine
https://www.nature.com/articles/s12276-023-01042-9
Dysbiosis in IBD patients is evident in that a decrease in the bacterial diversity and an increase in the composition of certain virulent bacteria could exaggerate the immune response. […] The gut microbiota in PSC patients has been found to be functionally different than that in healthy controls, exhibiting a decreased level of vitamin B6 and branched-chain amino acids. […] Therefore, K. pneumoniae may induce hepatobiliary tract damage secondary to inducing the hepatic Th17 cell-mediated immune response. […] Alterations in the gut microbiota in PSC might be a secondary event in the disease, whereas the gut microbiota is also involved and has an active part in disease progression through aspects involving gut barrier dysfunction and the translocation of virulent bacteria and toxins.
#24 Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gutâliver axis | Experimental & Molecular Medicine
https://www.nature.com/articles/s12276-023-01042-9
Dysbiosis in IBD patients is evident in that a decrease in the bacterial diversity and an increase in the composition of certain virulent bacteria could exaggerate the immune response. […] The gut microbiota in PSC patients has been found to be functionally different than that in healthy controls, exhibiting a decreased level of vitamin B6 and branched-chain amino acids. […] Therefore, K. pneumoniae may induce hepatobiliary tract damage secondary to inducing the hepatic Th17 cell-mediated immune response. […] Alterations in the gut microbiota in PSC might be a secondary event in the disease, whereas the gut microbiota is also involved and has an active part in disease progression through aspects involving gut barrier dysfunction and the translocation of virulent bacteria and toxins.
#25 Primary sclerosing cholangitis – Rabiee – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/6491/html
Inflammation and fibrosis lead to cholestasis and parenchymal injury. A distinct bile acid profile has been noted in IBD-PSC patients with a direct toxic effect of bile acids on cholangiocytes believed to contribute to disease progression. Primary or secondary disturbances in bile homeostasis as part of disease processes in the bile ducts or the colon, or deficiencies in protective or compensatory mechanisms, such as the so-called bicarbonate umbrella have been implicated in the pathogenesis of PSC. The cholangiocytes show an activated phenotype in PSC, which may further trigger an immune response through interactions with hepatic stellate cells and/or portal myofibroblasts, promoting development of peribiliary fibrosis and eventually cirrhosis.
#26 Primary sclerosing cholangitis – Rabiee – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/6491/html
Inflammation and fibrosis lead to cholestasis and parenchymal injury. A distinct bile acid profile has been noted in IBD-PSC patients with a direct toxic effect of bile acids on cholangiocytes believed to contribute to disease progression. Primary or secondary disturbances in bile homeostasis as part of disease processes in the bile ducts or the colon, or deficiencies in protective or compensatory mechanisms, such as the so-called bicarbonate umbrella have been implicated in the pathogenesis of PSC. The cholangiocytes show an activated phenotype in PSC, which may further trigger an immune response through interactions with hepatic stellate cells and/or portal myofibroblasts, promoting development of peribiliary fibrosis and eventually cirrhosis.
#27
https://www.xiahepublishing.com/2310-8819/JCTH-2022-00068S
The localization of hepatic inflammation to the biliary tree in PSC suggests that bile acid disturbance or microbial colonization might contribute to its underlying pathophysiology. This is supported by the identification of non-HLA susceptibility loci in PSC patients related to the regulation of bile acid and bicarbonate secretion. […] In PSC, there is interest in the manipulation of nuclear receptors involved in the regulation of bile acid production, transport and metabolism via hydroxylation and conjugation to less toxic compounds. Potential nuclear receptors of interest include the Farnesoid X receptor (FXR), pregnane X receptor (PXR), vitamin D receptor and constitutive androstane receptor. […] The FXR/fibroblast growth factor (FGF)19 pathway is a negative feedback mechanism that regulates bile acid production and uptake. Activation of FXR by bile salts in the small intestine results in production of FGF19 that binds to fibroblast growth factor receptor 4 (FGFR4)/beta-Klotho complex in the liver. This leads to CYP7A1 downregulation and subsequent reduction in synthesis of bile acids.
#28 Primary sclerosing cholangitis – Rabiee – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/6491/html
Inflammation and fibrosis lead to cholestasis and parenchymal injury. A distinct bile acid profile has been noted in IBD-PSC patients with a direct toxic effect of bile acids on cholangiocytes believed to contribute to disease progression. Primary or secondary disturbances in bile homeostasis as part of disease processes in the bile ducts or the colon, or deficiencies in protective or compensatory mechanisms, such as the so-called bicarbonate umbrella have been implicated in the pathogenesis of PSC. The cholangiocytes show an activated phenotype in PSC, which may further trigger an immune response through interactions with hepatic stellate cells and/or portal myofibroblasts, promoting development of peribiliary fibrosis and eventually cirrhosis.
#29 Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gutâliver axis | Experimental & Molecular Medicine
https://www.nature.com/articles/s12276-023-01042-9
However, hepatic inflammation can be caused independently from gut inflammation. […] Interestingly, the expression of MAdCAM-1 and vascular adhesion protein 1 (VAP-1) along with CCL25 secretion are shared in the digestive and hepatic systems of PSC patients, which enables activated T cells to bind to both the intestinal mucosa and hepatic endothelium. […] The signaling of BAs involves a series of receptors, including membrane-bound G protein-coupled receptor (TGR5) and the nuclear receptor farnesoid X receptor (FXR). […] Primary BAs are converted to bioactive molecules by enzymes of the gut microbiota, and bioactive metabolites serve as substrates for microbiota metabolism, modulate the balance of Th17 and Tregs, and inhibit bacterial growth. […] Therefore, there is reciprocal action between BA metabolism and the gut microbiota.
#30
https://www.omim.org/entry/613806
Using flow cytometry, Eksteen et al. (2004) found substantially increased expression of CCR9 (604738) on liver-infiltrating lymphocytes (LILs) in patients with primary sclerosing cholangitis compared with organ donor controls and patients with other chronic inflammatory liver diseases. […] Immunohistochemical and Western blot analyses demonstrated that CCL25 (602565), which is normally expressed in thymus and intestine only, was highly expressed in livers of PSC patients but not other liver disease patients. […] Eksteen et al. (2004) proposed that T cells activated in the gut during active inflammatory bowel disease differentiate into effector cells with the ability to bind to both hepatic and mucosal endothelium. They suggested that CCL25 and MADCAM1 cooperate in recruiting mucosal CCR9-positive lymphocytes to the liver in PSC.
#31 Primary sclerosing cholangitis – Rabiee – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/6491/html
The strong HLA associations found in genetic studies suggest that adaptive immune responses are involved. The HLA class I and class II molecules present potentially antigenic peptides, derived from intracellular and extracellular sources, respectively, to the T cell receptor on CD8 and CD4 positive T cells. Gut derived antigens presented by PSC-associated HLA variants to the T cell receptor are potential triggers of these responses, and activated T cells may migrate to both the liver and gut following clonal expansion because of the overlapping expression in the gut and the liver of relevant lymphocyte homing components including mucosal vascular address in cell adhesion molecule 1 (MadCAM-1) and vascular cell adhesion molecule 1 (VCAM-1), 47 integrin, along with Chemokine C-C motif ligand 25 (CCL25) secretion, and contribute to the pathogenesis of PSC. In the liver, these recruited lymphocytes have been implicated in biliary inflammation leading to apoptosis and necrosis of cholangiocytes, and eventually fibrosis.
#32 Primary sclerosing cholangitis – Rabiee – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/6491/html
The strong HLA associations found in genetic studies suggest that adaptive immune responses are involved. The HLA class I and class II molecules present potentially antigenic peptides, derived from intracellular and extracellular sources, respectively, to the T cell receptor on CD8 and CD4 positive T cells. Gut derived antigens presented by PSC-associated HLA variants to the T cell receptor are potential triggers of these responses, and activated T cells may migrate to both the liver and gut following clonal expansion because of the overlapping expression in the gut and the liver of relevant lymphocyte homing components including mucosal vascular address in cell adhesion molecule 1 (MadCAM-1) and vascular cell adhesion molecule 1 (VCAM-1), 47 integrin, along with Chemokine C-C motif ligand 25 (CCL25) secretion, and contribute to the pathogenesis of PSC. In the liver, these recruited lymphocytes have been implicated in biliary inflammation leading to apoptosis and necrosis of cholangiocytes, and eventually fibrosis.
#33
https://link.springer.com/article/10.1007/s00535-020-01681-z
In the liver, these recruited lymphocytes have been suggested to involve in the biliary inflammation leading to apoptosis and necrosis of cholangiocytes, and with time tissue fibrosis. […] Gut-derived antigens presented by PSC-associated human leukocyte antigen (HLA) variants to the T cell receptor (TCR) may also contribute to adaptive immune responses in the portal areas by means of molecular mimicry. […] Furthermore, a series of studies now strongly indicate that the gut microbiota may be involved in PSC pathogenesis giving rise to clinical trials involving fecal transplantation, non-absorbable antibiotics, and other means of manipulating the gut microbiome in patients. […] Toxic effects of bile upon cholangiocytes, due to cholestasis, or primary or secondary changes in bile composition as part of disease processes in the bile ducts or colon, or impairment of protective means may contribute to biliary inflammatory and fibrotic processes.
#34
https://link.springer.com/article/10.1007/s00281-009-0154-7
Several working models have been proposed to explain many of the peculiar features of PSC, namely, the strong association with IBD, the observation that PSC may develop after total colectomy and that the liver disease activity of PSC does not correlate with the intestinal disease activity of IBD. […] Vierling proposed that the immunopathogenesis of PSC involves multiple steps starting with the activation of a cholangiocyte by a bacterial pathogen that translocates to the liver from the gut. […] The second hypothesis addresses how intestinal mucosal lymphocytes home to the liver. This theory suggests that lymphocytes are activated in the bowel of IBD patients and then aberrantly recruited to extraintestinal sites. […] A third theory recently introduced by Fickert et al. compares the pathogenesis of PSC to arteriosclerosis.
#35
https://link.springer.com/article/10.1007/s00281-009-0154-7
Several working models have been proposed to explain many of the peculiar features of PSC, namely, the strong association with IBD, the observation that PSC may develop after total colectomy and that the liver disease activity of PSC does not correlate with the intestinal disease activity of IBD. […] Vierling proposed that the immunopathogenesis of PSC involves multiple steps starting with the activation of a cholangiocyte by a bacterial pathogen that translocates to the liver from the gut. […] The second hypothesis addresses how intestinal mucosal lymphocytes home to the liver. This theory suggests that lymphocytes are activated in the bowel of IBD patients and then aberrantly recruited to extraintestinal sites. […] A third theory recently introduced by Fickert et al. compares the pathogenesis of PSC to arteriosclerosis.
#36
https://link.springer.com/article/10.1007/s00281-009-0154-7
Several working models have been proposed to explain many of the peculiar features of PSC, namely, the strong association with IBD, the observation that PSC may develop after total colectomy and that the liver disease activity of PSC does not correlate with the intestinal disease activity of IBD. […] Vierling proposed that the immunopathogenesis of PSC involves multiple steps starting with the activation of a cholangiocyte by a bacterial pathogen that translocates to the liver from the gut. […] The second hypothesis addresses how intestinal mucosal lymphocytes home to the liver. This theory suggests that lymphocytes are activated in the bowel of IBD patients and then aberrantly recruited to extraintestinal sites. […] A third theory recently introduced by Fickert et al. compares the pathogenesis of PSC to arteriosclerosis.
#37
https://link.springer.com/article/10.1007/s00281-009-0154-7
Several working models have been proposed to explain many of the peculiar features of PSC, namely, the strong association with IBD, the observation that PSC may develop after total colectomy and that the liver disease activity of PSC does not correlate with the intestinal disease activity of IBD. […] Vierling proposed that the immunopathogenesis of PSC involves multiple steps starting with the activation of a cholangiocyte by a bacterial pathogen that translocates to the liver from the gut. […] The second hypothesis addresses how intestinal mucosal lymphocytes home to the liver. This theory suggests that lymphocytes are activated in the bowel of IBD patients and then aberrantly recruited to extraintestinal sites. […] A third theory recently introduced by Fickert et al. compares the pathogenesis of PSC to arteriosclerosis.
#38 Pathogenesis and clinical spectrum of primary sclerosing cholangitis
https://www.wjgnet.com/1007-9327/full/v23/i14/2459.htm
Numerous studies have attempted to identify specific genes, which either predispose or protect an individual from the development of PSC. […] Due to the association of IBD with PSC, a leaky gut hypothesis has also been postulated. […] Immune activation to an antigen (or a cross-reactive autoantigen or an enteric microbiome) also leads to inflammation of the gut and of the biliary tree. […] A critical driver of disease development may be an altered biliary mucosal milieu, giving rise to biliary colonization of non-commensal bacteria. […] The pathogenesis of PSC is likely the result of an amalgamation of a heightened immune response to a pathogen in a host with both an altered biliary mucosal milieu and a genetic predisposition to PSC.
#39 What Is the Pathogenesis of Acute Sclerosing Cholangitis?
https://www.icliniq.com/articles/liver-diseases/acute-sclerosing-cholangitis
Acute sclerosing cholangitis is closely associated with inflammatory bowel disease. Researchers have developed a leaky gut hypothesis, which suggests the association of inflammatory bowel disease with acute sclerosing cholangitis. […] The intestinal flora migrates from the infected gastrointestinal tract to the portal venous system resulting in an inflammatory response that disrupts the biliary epithelial cells. As a result, the bile acids act on cholangiocytes (epithelial cells of the bile duct that secret and modify bile) and cause injury and inflammation of the bile duct. Immune response to an antigen causes inflammation of the bile duct and intestine. […] Myofibroblasts are activated due to cytokines, tumor necrosis factor, interleukin, transforming growth factor, CD4, and CD8 cells cause and result in an inflammatory response and tissue fibrosis.
#40 Pathogenesis of primary sclerosing cholangitis
https://pmc.ncbi.nlm.nih.gov/articles/PMC3236286/
Consequently, inflammatory cells, such as macrophages, dentritic cells (DCs), and NK cells are activated through pattern recognition receptors, secrete cytokines and perpetuate inflammatory reaction by activation of NK cells through IL-12 and recruitment of lymphocytes via TNF-, IL-1 and CXCL8. […] Biliary epithelial cells (BECs) have an active role in propagating the proinflammatory and profibrotic response. […] Taken together, the general problem of defining cell response in PSC can be attributed to the difficult detection of early PSC lesions in representative tissues.
#41 Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gutâliver axis | Experimental & Molecular Medicine
https://www.nature.com/articles/s12276-023-01042-9
In summary, the genetic predisposition for PSC seems to involve HLA genes and genes related to T cells, BA homeostasis, and other inflammatory conditions. […] The pathogenesis of PSC-IBD involves the perturbation of both innate and adaptive immunity. […] Cholangiocytes are exceptionally sensitive to systemic immune conditions and have an active role in cultivating the proinflammatory and profibrotic response. […] Given the strong link between PSC and IBD, cholangiocytes in PSC may be exposed to an increased amount of LPS or other antigens released from the inflamed gut, which then triggers TLR-mediated signaling. […] Thus, intestinal inflammation causes increased leakage of LPS and may cause biliary damage in a genetically susceptible host through the LPSTLR4NF-B axis pathway. […] The strong linkage between PSC and IBD implies hepatic inflammation originating in the intestine.
#42 Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gutâliver axis | Experimental & Molecular Medicine
https://www.nature.com/articles/s12276-023-01042-9
In summary, the genetic predisposition for PSC seems to involve HLA genes and genes related to T cells, BA homeostasis, and other inflammatory conditions. […] The pathogenesis of PSC-IBD involves the perturbation of both innate and adaptive immunity. […] Cholangiocytes are exceptionally sensitive to systemic immune conditions and have an active role in cultivating the proinflammatory and profibrotic response. […] Given the strong link between PSC and IBD, cholangiocytes in PSC may be exposed to an increased amount of LPS or other antigens released from the inflamed gut, which then triggers TLR-mediated signaling. […] Thus, intestinal inflammation causes increased leakage of LPS and may cause biliary damage in a genetically susceptible host through the LPSTLR4NF-B axis pathway. […] The strong linkage between PSC and IBD implies hepatic inflammation originating in the intestine.
#43 Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gutâliver axis | Experimental & Molecular Medicine
https://www.nature.com/articles/s12276-023-01042-9
In summary, the genetic predisposition for PSC seems to involve HLA genes and genes related to T cells, BA homeostasis, and other inflammatory conditions. […] The pathogenesis of PSC-IBD involves the perturbation of both innate and adaptive immunity. […] Cholangiocytes are exceptionally sensitive to systemic immune conditions and have an active role in cultivating the proinflammatory and profibrotic response. […] Given the strong link between PSC and IBD, cholangiocytes in PSC may be exposed to an increased amount of LPS or other antigens released from the inflamed gut, which then triggers TLR-mediated signaling. […] Thus, intestinal inflammation causes increased leakage of LPS and may cause biliary damage in a genetically susceptible host through the LPSTLR4NF-B axis pathway. […] The strong linkage between PSC and IBD implies hepatic inflammation originating in the intestine.
#44 Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma: From Pathogenesis to Diagnostic and Surveillance Strategies
https://www.mdpi.com/2072-6694/15/20/4947
In chronic inflammation, cholangiocytes manifest a high proliferative capacity as an adaptative response to prevent ductopenia, and could also act as facultative liver stem cells in case of important liver damage. […] Previous studies have already described the presence of p53 dysfunction as the most common aberration in PSC-CCA, usually occurring in up to 30% of cases, more frequently than sporadic CCA. […] An important role in cellular damage is played by biliary infections, promoting oxidative stress of cholangiocytes. […] Genetic and epigenetic factors could contribute to PSC-CCA developments. […] The analysis of micro ribonucleic acid (miRNAs) was highly investigated. miRNAs represent non-coding small nucleic acids capable of binding to specifical messenger RNA (mRNAs) and regulating gene expression. […] The current pathogenetic knowledge of PSC-CCA highlights how it appears to be a different entity from sporadic CCA and explains why it is characterized by a unique clinical presentation and epidemiology.
#45 Pathology Pearls Post 8: Primary Sclerosing Cholangitis (PSC) | AASLD
https://www.aasld.org/liver-fellow-network/core-series/pathology-pearls/pathology-pearls-post-8-primary-sclerosing
Given the absence of etiology for secondary cholangitis such as infection and neoplasia, the histologic findings are suggestive of primary sclerosing cholangitis (PSC). […] The most classic findings of PSC include large bile ducts surrounded by concentric fibrosis, which is also referred to as onion skin fibrosis. […] As the disease progresses there is bile duct loss (ductopenia) and fibro-obliterative lesions or scars replace the bile ducts in portal tracts. […] Bile duct injury may be present; however, the severity depends upon disease duration. Examples of bile duct injury include cytoplasmic vacuolization, epithelial attenuation, and nuclear disarray. Increased intraepithelial lymphocytes may also be identified. Further, secondary changes due to bile duct obstruction may be seen including cholate stasis, bile ductular proliferation, and periportal copper deposition. Over time, chronic injury may result in biliary type cirrhosis typically described as a jigsaw puzzle pattern.
#46 Pathology Pearls Post 8: Primary Sclerosing Cholangitis (PSC) | AASLD
https://www.aasld.org/liver-fellow-network/core-series/pathology-pearls/pathology-pearls-post-8-primary-sclerosing
Given the absence of etiology for secondary cholangitis such as infection and neoplasia, the histologic findings are suggestive of primary sclerosing cholangitis (PSC). […] The most classic findings of PSC include large bile ducts surrounded by concentric fibrosis, which is also referred to as onion skin fibrosis. […] As the disease progresses there is bile duct loss (ductopenia) and fibro-obliterative lesions or scars replace the bile ducts in portal tracts. […] Bile duct injury may be present; however, the severity depends upon disease duration. Examples of bile duct injury include cytoplasmic vacuolization, epithelial attenuation, and nuclear disarray. Increased intraepithelial lymphocytes may also be identified. Further, secondary changes due to bile duct obstruction may be seen including cholate stasis, bile ductular proliferation, and periportal copper deposition. Over time, chronic injury may result in biliary type cirrhosis typically described as a jigsaw puzzle pattern.
#47 Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma: From Pathogenesis to Diagnostic and Surveillance Strategies
https://www.mdpi.com/2072-6694/15/20/4947
Regarding PSC-CCA, the pathogenetic mechanisms are not fully understood; immune-mediated hits and bile stasis might lead to chronic inflammation and cancerogenesis. […] The most supported model of biliary carcinogenesis is the âmultistep carcinogenesisâ model. Presence of chronic inflammation leads to the sequential progression from damaged normal biliary epithelium to low-grade dysplasia (LGD), high-grade dysplasia (HGD), and finally invasive cancer. […] A higher frequency of metaplasia and dysplasia was observed in the explanted liver of patients who developed PSC-CCA than PSC alone, suggesting that these histological findings could anticipate CCA development. […] Intestinal metaplasia represents a significant predictor of both dysplasia and CCA, confirming the existence of a multistep process of neoplastic transformation and partially differentiating the pathogenesis of PSC-CCA from CCA alone.
#48 Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma: From Pathogenesis to Diagnostic and Surveillance Strategies
https://www.mdpi.com/2072-6694/15/20/4947
Regarding PSC-CCA, the pathogenetic mechanisms are not fully understood; immune-mediated hits and bile stasis might lead to chronic inflammation and cancerogenesis. […] The most supported model of biliary carcinogenesis is the âmultistep carcinogenesisâ model. Presence of chronic inflammation leads to the sequential progression from damaged normal biliary epithelium to low-grade dysplasia (LGD), high-grade dysplasia (HGD), and finally invasive cancer. […] A higher frequency of metaplasia and dysplasia was observed in the explanted liver of patients who developed PSC-CCA than PSC alone, suggesting that these histological findings could anticipate CCA development. […] Intestinal metaplasia represents a significant predictor of both dysplasia and CCA, confirming the existence of a multistep process of neoplastic transformation and partially differentiating the pathogenesis of PSC-CCA from CCA alone.
#49 Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma: From Pathogenesis to Diagnostic and Surveillance Strategies
https://www.mdpi.com/2072-6694/15/20/4947
Regarding PSC-CCA, the pathogenetic mechanisms are not fully understood; immune-mediated hits and bile stasis might lead to chronic inflammation and cancerogenesis. […] The most supported model of biliary carcinogenesis is the âmultistep carcinogenesisâ model. Presence of chronic inflammation leads to the sequential progression from damaged normal biliary epithelium to low-grade dysplasia (LGD), high-grade dysplasia (HGD), and finally invasive cancer. […] A higher frequency of metaplasia and dysplasia was observed in the explanted liver of patients who developed PSC-CCA than PSC alone, suggesting that these histological findings could anticipate CCA development. […] Intestinal metaplasia represents a significant predictor of both dysplasia and CCA, confirming the existence of a multistep process of neoplastic transformation and partially differentiating the pathogenesis of PSC-CCA from CCA alone.
#50 Pathogenesis of primary sclerosing cholangitis
https://pmc.ncbi.nlm.nih.gov/articles/PMC3236286/
Primary sclerosing cholangitis (PSC) represents a chronic cholestatic liver disease with fibroobliterative sclerosis of intra- and/or extrahepatic bile ducts, eventually leading to biliary cirrhosis. […] The association with human leukocyte antigen (HLA) and non-HLA haplotypes and the presence of autoantibodies in sera of PSC patients support a crucial role for immune-mediated mechanisms in the initiation and progression of PSC. […] Genetically or chemically modified bile composition was shown to induce sclerosing cholangitis and liver fibrosis in a number of animal models („toxic bile concept”). […] The potential role of vascular injury with ischemia of bile duct epithelium cells in the development of sclerosing cholangitis is supported by animal models of endothelial cell injury showing close morphological similarities with human PSC.
#51 Pathogenesis and clinical spectrum of primary sclerosing cholangitis
https://www.wjgnet.com/1007-9327/full/v23/i14/2459.htm
Numerous studies have attempted to identify specific genes, which either predispose or protect an individual from the development of PSC. […] Due to the association of IBD with PSC, a leaky gut hypothesis has also been postulated. […] Immune activation to an antigen (or a cross-reactive autoantigen or an enteric microbiome) also leads to inflammation of the gut and of the biliary tree. […] A critical driver of disease development may be an altered biliary mucosal milieu, giving rise to biliary colonization of non-commensal bacteria. […] The pathogenesis of PSC is likely the result of an amalgamation of a heightened immune response to a pathogen in a host with both an altered biliary mucosal milieu and a genetic predisposition to PSC.
#52 Primary Sclerosing Cholangitis: Background, Etiopathophysiology, Epidemiology
https://emedicine.medscape.com/article/931355-overview
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by a progressive course of cholestasis with inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. The underlying cause of the inflammation is believed to be autoimmune. […] An autoimmune mechanism is suggested, because approximately 70% of patients with PSC have inflammatory bowel disease (IBD). However, only approximately 4% of patients with IBD have or develop PSC. A marked increase in serum autoantibody levels occurs in patients with PSC as well, with antineutrophil cytoplasmic antibodies (ANCA) in 87%, anticardiolipin (aCL) antibodies in 66%, and antinuclear antibodies (ANA) in 53%. It has been reported that PSC and IBD have overlapping yet distinct genetic architectures. […] In the biliary ducts, an inflammatory response to chronic or recurrent bacterial infection in the portal circulation and from exposure to toxic bile acids has been postulated. A genetic predisposition has been suggested because of an increased prevalence of HLA-B8, HLA-DR3, and HLA-Drw52a. Genome-wide association studies (GWAS) performed in PSC have identified about 20 genes that are significantly associated with PSC, most of which localize within the human leukocyte antigen (HLA) complex. […] Therefore, the most plausible concept of the pathogenesis of PSC involves the exposure of genetically predisposed individuals to an environmental antigen that subsequently elicits an aberrant immune response, leading to development of the disease.
#53 Pathogenesis of primary sclerosing cholangitis
https://pmc.ncbi.nlm.nih.gov/articles/PMC3236286/
Primary sclerosing cholangitis (PSC) represents a chronic cholestatic liver disease with fibroobliterative sclerosis of intra- and/or extrahepatic bile ducts, eventually leading to biliary cirrhosis. […] The association with human leukocyte antigen (HLA) and non-HLA haplotypes and the presence of autoantibodies in sera of PSC patients support a crucial role for immune-mediated mechanisms in the initiation and progression of PSC. […] Genetically or chemically modified bile composition was shown to induce sclerosing cholangitis and liver fibrosis in a number of animal models („toxic bile concept”). […] The potential role of vascular injury with ischemia of bile duct epithelium cells in the development of sclerosing cholangitis is supported by animal models of endothelial cell injury showing close morphological similarities with human PSC.
#54 Pathogenesis of primary sclerosing cholangitis
https://pmc.ncbi.nlm.nih.gov/articles/PMC3236286/
Primary sclerosing cholangitis (PSC) represents a chronic cholestatic liver disease with fibroobliterative sclerosis of intra- and/or extrahepatic bile ducts, eventually leading to biliary cirrhosis. […] The association with human leukocyte antigen (HLA) and non-HLA haplotypes and the presence of autoantibodies in sera of PSC patients support a crucial role for immune-mediated mechanisms in the initiation and progression of PSC. […] Genetically or chemically modified bile composition was shown to induce sclerosing cholangitis and liver fibrosis in a number of animal models („toxic bile concept”). […] The potential role of vascular injury with ischemia of bile duct epithelium cells in the development of sclerosing cholangitis is supported by animal models of endothelial cell injury showing close morphological similarities with human PSC.
#55
https://link.springer.com/article/10.1007/s00535-020-01681-z
Primary sclerosing cholangitis (PSC) is a progressive liver disease, histologically characterized by inflammation and fibrosis of the bile ducts, and clinically leading to multi-focal biliary strictures and with time cirrhosis and liver failure. […] Advances in our understanding of PSC pathogenesis and biliary physiology over recent years has however led to a surge of clinical trials targeting various mechanistic compartments and currently raising hopes for imminent changes in patient management. […] A major challenge in identifying effective therapeutic approaches is that a proven conceptual framework is still lacking for PSC pathogenesis. The pathogenesis of PSC currently appears complex, many-facetted and with an incomplete understanding of primary versus secondary processes, leaving critical knowledge gaps in the selection of potential therapeutic targets.
#56
https://www.jci.org/articles/view/174218
Another study showed that the FGF15/-19/FXR/CYP7A1 axis had a key role in modulating BA synthesis. […] TGR5 is a GPCR for primary and secondary BAs and was shown to have a protective role in biliary epithelial cells (BECs) by stimulating tight junction integrity. […] Taken together, these preclinical studies provide a strong rationale to pursue clinical trials. […] Despite tremendous efforts to define the key pathogenic features and therapeutic targets, effective medical therapy for PSC is still lacking. […] We are now beginning to understand the early triggering events, such as the role of microbiota and mucosal immunity and their effects on innate immunity in PSC. […] With all the recent discoveries, effective medical therapy is expected to be available in the next few years.