Wrzodziejące zapalenie przełyku barretta – Patofizjologia i mechanizm

Wrzodziejące zapalenie przełyku barretta
Patofizjologia i mechanizm

Przełyk Barretta to stan przedrakowy charakteryzujący się metaplazją nabłonka wielowarstwowego płaskiego przełyku w nabłonek walcowaty typu jelitowego, ściśle powiązany z przewlekłą chorobą refluksową przełyku (GERD) i stanowiący główny czynnik ryzyka gruczolakoraka przełyku. Proces rozwoju przełyku Barretta przebiega dwuetapowo: początkowa transformacja nabłonka płaskiego w błonę śluzową wpustu, a następnie powolny rozwój komórek kubkowych metaplazji jelitowej w ciągu 5-10 lat. Mechanizmy molekularne obejmują ekspozycję na kwas i sole żółciowe w pH 3-6, co prowadzi do uszkodzenia komórek, aktywacji cytokin zapalnych (IL-8, IL-1β), wzrostu ekspresji CDX2 i MUC2 oraz stresu oksydacyjnego. Kluczowe szlaki sygnałowe zaangażowane w metaplazję to NF-κB, SHH-BMP4, Notch, WNT i kwas retinowy, które modulują różnicowanie i proliferację komórek nabłonka przełyku. Geny takie jak CDX2, TP53 oraz mutacje w genie supresorowym p16 są wczesnymi markerami molekularnymi progresji do dysplazji i raka.

Patogeneza przełyku Barretta

Proces dwuetapowy w rozwoju przełyku Barretta
Mechanizmy molekularne w patogenezie
Rola kwasu i żółci w patogenezie

Rola szlaków sygnałowych w patogenezie przełyku Barretta

Szlak NF-κB i rola cytokin
Szlaki NOTCH, BMP i Hedgehog
Rola czynników transkrypcyjnych

Zmiany genetyczne i niestabilność genomowa w przełyku Barretta

Teoria komórek macierzystych w patogenezie
Nabłonek wielowarstwowy jako pośredni etap metaplazji

Czynniki ryzyka i predyspozycje do rozwoju przełyku Barretta
Progresja przełyku Barretta do gruczolakoraka

Biomarkery predykcyjne progresji
Wpływ leczenia na progresję przełyku Barretta

Aktualne zrozumienie patogenezy przełyku Barretta

Kolejne rozdziały

Patogeneza przełyku Barretta

Wrzodziejące zapalenie przełyku Barretta to stan przedrakowy, charakteryzujący się metaplazją nabłonka wielowarstwowego płaskiego przełyku w nabłonek walcowaty typu jelitowego. Stan ten jest ściśle związany z przewlekłą chorobą refluksową przełyku (GERD) i stanowi główny czynnik ryzyka rozwoju gruczolakoraka przełyku.¹²³

Proces dwuetapowy w rozwoju przełyku Barretta

Rozwój przełyku Barretta to prawdopodobnie proces dwuetapowy. Pierwszy etap polega na transformacji prawidłowego nabłonka płaskiego przełyku w prosty nabłonek walcowaty, nazywany błoną śluzową wpustu (cardiac mucosa). Proces ten zachodzi stosunkowo szybko, w ciągu kilku lat, w odpowiedzi na przewlekłe uszkodzenie spowodowane powtarzającymi się epizodami refluksu treści żołądkowej na błonę śluzową przełyku.¹²³

Drugi etap, rozwijający się znacznie wolniej (przez około 5-10 lat), obejmuje rozwój komórek kubkowych charakterystycznych dla metaplazji jelitowej. Gdy pojawia się widoczny endoskopowo odcinek takiej błony śluzowej w przełyku, spełniona zostaje definicja przełyku Barretta. Po wystąpieniu, przełyk Barretta może postępować do dysplazji niskiego i wysokiego stopnia, a ostatecznie do gruczolakoraka. Cały ten proces jest często opisywany jako sekwencja metaplazja-dysplazja-rak przełyku Barretta.¹²³

Mechanizmy molekularne w patogenezie

Dokładne szczegóły mechanizmu molekularnego, w którym nabłonek płaski przekształca się w błonę śluzową wpustu, pozostają nieznane. Jednakże istnieje prawdopodobnie kluczowa interakcja między normalnie sekwestrowanymi komórkami macierzystymi przełyku a bodźcem wewnątrzświatłowym, który napędza ten proces metaplastyczny.¹

Badania wykazały, że ekspozycja nabłonka płaskiego przełyku na treść żołądkową powoduje rozszerzenie przestrzeni międzykomórkowych, co pozwala cząsteczkom o wielkości do 20 kDa przenikać do komórek macierzystych w warstwie podstawnej. Ten mechanizm zwiększa przepuszczalność nabłonka, umożliwiając większym cząsteczkom dyfuzję, co prowadzi do ekspozycji komórek macierzystych warstwy podstawnej na płyn refluksowy i uruchamia kaskadę zdarzeń prowadzących do obrzęku komórek i ostatecznie śmierci komórki.¹²³

Rola kwasu i żółci w patogenezie

Przypuszcza się, że mechanizm, w którym kwas i żółć współdziałają w powstawaniu przełyku Barretta, jest związany ze stanem jonizacji soli żółciowych. W środowisku słabo kwaśnym (pH 3-6) niektóre kwasy żółciowe są szczególnie toksyczne. W tym zakresie pH sole żółciowe są rozpuszczalne i niezjonizowane, mogą wnikać do komórek błony śluzowej, gromadzić się i powodować bezpośrednie uszkodzenie komórek.¹

Ekspozycja na kwas powoduje, że komórki nabłonka płaskiego wydzielają cytokiny zapalne, takie jak interleukina 8 i interleukina 1b, które pośredniczą w odpowiedzi zapalnej i sygnalizują limfocytom T i neutrofilom migrację do nabłonka. Kwasy żółciowe, w szczególności, wykazano, że zwiększają ekspresję CDX2, czynnika różnicowania jelitowego, oraz MUC2, genu specyficznego dla komórek kubkowych, w obrębie normalnych linii komórkowych walcowatych i komórek raka przełyku.¹²

Jednocześnie powtarzająca się ekspozycja na kwas i żółć powoduje uszkodzenia organelli komórkowych, w tym błon mitochondrialnych, co wywołuje niekontrolowane generowanie reaktywnych form tlenu, stres oksydacyjny i uszkodzenia DNA. Rozwój metaplazji jelitowej jest zatem mechanizmem adaptacyjnym w dystalnej części przełyku.¹

Rola szlaków sygnałowych w patogenezie przełyku Barretta

Szlak NF-κB i rola cytokin

Klasyczna koncepcja gojenia się uszkodzenia żrącego została zastąpiona koncepcją „burzy cytokinowej”, która tworzy mikrośrodowisko zapalne wywołujące zmianę fenotypową w kierunku metaplazji jelitowej dystalnej części przełyku.¹

Aktywacja czynnika jądrowego kappa B (NF-κB) w dystalnej części przełyku nie tylko prowadzi do przewlekłego zapalenia, ale także indukuje rozwój metaplazji jelitowej poprzez aktywację CDX2, który ma kluczowe znaczenie dla różnicowania jelitowego. Poziomy IL-8 i IL-1β wzrastają od erozyjnego zapalenia przełyku do przełyku Barretta, a następnie do gruczolakoraka przełyku, a poziomy NF-κB jednocześnie rosną, prowadząc do proliferacji komórek nabłonkowych, zapobiegania apoptozie i promowania karcynogenezy.¹²

Koncepcja uszkodzenia błony śluzowej dystalnej części przełyku wywołanego refluksem i mediowanego przez cytokiny została zaproponowana przez Souza R.F. i wsp., którzy stwierdzili, że u szczurów z ezofagoduodenoanastomozą owrzodzenia pojawiły się kilka tygodni po operacji, a więc nie były inicjowane bezpośrednio przez kwas i refluksem żółci poprzez uszkodzenie żrące.¹

Szlaki NOTCH, BMP i Hedgehog

Ważne postępy zostały poczynione w zrozumieniu podstawowych mechanizmów molekularnych w procesie metaplazji Barretta. Obecna hipoteza zakłada, że stopniowy rozwój metaplazji jelitowej opiera się na zwiększonej regulacji różnych szlaków sygnałowych, w tym SHH, WNT, Notch, kwasu retinowego (RA) i białka morfogenetycznego kości (BMP), które normalnie uczestniczą w rozwoju i homeostazie jelit i innych narządów.¹²

Obecna koncepcja metaplazji przełyku zakłada, że przewlekłe uszkodzenie zapalne spowodowane refluksem żółci i kwasu, jak obserwuje się w chorobie refluksowej przełyku, doprowadziło do zwiększonej regulacji lub odnowionej ekspresji szlaku sygnałowego SHH-BMP4, który zmienia środowisko nabłonkowe na korzyść komórek walcowatych lub kieruje komórki w stronę fenotypu walcowatego.¹²

W biopsjach przełyku Barretta SHH i jego receptor PTCH są zwiększone. Również BMP4 i jego docelowy pSMAD są wysoko wyrażone, podczas gdy ekspresja Noggin, jego naturalnego inhibitora, jest niska.¹²

Szlak sygnałowy Notch działa jako fundamentalny molekularny system sygnalizacyjny, który kontroluje decyzje dotyczące losów komórek, takie jak różnicowanie, proliferacja i apoptoza, w prawie wszystkich typach tkanki. Ostatnie odkrycia ujawniły związek między sygnalizacją Notch a ekspresją CDX2. Stwierdzono, że hamowanie szlaku Notch przez kwasy żółciowe w komórkach przełyku koreluje ze zwiększeniem Hath1 i CDX2 i może być jednym z kluczowych procesów przyczyniających się do powstawania przełyku Barretta.¹²

Rola czynników transkrypcyjnych

Molekularne mechanizmy, poprzez które błona śluzowa wpustu nabywa komórki kubkowe, pozostają do wyjaśnienia. Istnieją jednak coraz liczniejsze dowody na to, że ekspresja genu homeobox Cdx-2 odgrywa kluczową rolę. Ekspresja tego genu wzrasta wraz z progresją od nabłonka płaskiego z zapaleniem przełyku do błony śluzowej wpustu i jest maksymalna w warunkach metaplazji jelitowej.¹

W przypadku wsparcia procesu przeprogramowania molekularnego komórek progenitorowych płaskich przełyku, nieśmiertelne linie komórek płaskich przełyku i tkanki narażone na kwas i sole żółciowe in vitro lub GERD in vivo zwiększają swoją ekspresję czynników transkrypcyjnych kolumnowych SOX9 i białka forkhead box A2 (FOXA2), które są celami szlaku Hedgehog, oraz jelitowego czynnika transkrypcyjnego caudal-related homeobox transcription factor 2 (Cdx2), który jest celem szlaku (NF-κB).¹

Ekspozycja nabłonka przełyku na treść żołądkową generuje tlenek azotu (NO), który może inicjować przeprogramowanie progenitorów w przełyku poprzez hamowanie sygnalizacji Akt, powodując redukcję SOX2, zmniejszając izoformy TA i NP p63 oraz zwiększając regulację CDX2, co może prowadzić do rozwoju metaplazji jelitowej przełyku Barretta.¹

Zmiany genetyczne i niestabilność genomowa w przełyku Barretta

Powtarzająca się ekspozycja na kwasy żółciowe w kwaśnym pH powoduje stres oksydacyjny w nabłonkach płaskich i metaplastycznych w przełyku Barretta, prowadząc do uszkodzenia DNA, szczególnie pęknięć dwuniciowych.¹

Obciążenie mutacyjne w przełyku Barretta bez dysplazji jest bardzo zmienne i zostało oszacowane na 0,42-1,28 mutacji na Mb lub więcej. Obciążenie mutacyjne wzrasta w następujących warunkach, od najniższego do najwyższego: przełyk Barretta bez dysplazji, dysplazja niskiego stopnia, dysplazja wysokiego stopnia i gruczolakorak przełyku.¹

Dane te dostarczają dowodów na to, że katastrofa genomowa jest ważna w transformacji nowotworowej w przełyku Barretta, służąc jako alternatywny mechanizm karcynogenezy. Katastrofa genomowa często obserwowana w dysplazji wysokiego stopnia i gruczolakoraku przełyku prawdopodobnie wyjaśnia szybką progresję nowotworową w przełyku Barretta.¹

Do 90% dotkniętych pacjentów ma wykrywalną aberrację klonalną genu supresorowego guza p16. Mutacje CDX2 i TP53 są wczesnymi zmianami molekularnymi znajdowanymi w metaplastycznym nabłonku walcowatym nawet przed rozpoznaniem morfologicznej dysplazji. Jednak barwienie immunohistochemiczne w celu oceny tych markerów nie jest obecnie zalecane w rutynowych przypadkach diagnostycznych przełyku Barretta.¹²

Teoria komórek macierzystych w patogenezie

Najbardziej ugruntowana hipoteza dotycząca pochodzenia przełyku Barretta dotyczy zmiany kierunku różnicowania wielopotencjalnych komórek macierzystych i komórek progenitorowych. Jednakże różne komórki progenitorowe mogą być zaangażowane w patogenezę przełyku Barretta i mogą być odpowiedzialne za wszystkie fenotypy komórkowe metaplazji walcowatej, wyjaśniając w ten sposób heterogenność oraz policlonalne i mozaikowe rozprzestrzenianie się gruczołów metaplastycznych.¹²

Obiecującym źródłem komórek przełyku Barretta był migrujący nabłonek wpustu żołądka, który naprawia uszkodzenia spowodowane przez refluksowy wpływ treści żołądkowej na sąsiedni nabłonek przełyku. Obecnie uważa się, że przełyk Barretta rozwija się de novo z komórek wewnętrznych przełyku, a nie migrujących z żołądka.¹

Wiele doniesień sugeruje, że mieszanina kwasu żołądkowego i refluksu żółciowego aktywuje komórkę macierzystą przełyku do przekształcenia w nabłonek walcowaty typu jelitowego. Kandydaci na komórki macierzyste w przełyku obejmują komórki macierzyste zawarte w nabłonku przewodowym powierzchownych gruczołów wpustu lub gruczołów podśluzówkowych przełyku.¹

Teoria komórek macierzystych jest atrakcyjna, ponieważ wyjaśnia różnorodność fenotypów komórkowych występujących w przełyku Barretta, a także jak możliwa jest regeneracja podstawowej komórki macierzystej, i dobrze koreluje z pochodzeniem komórki wewnętrznej dla przełyku.¹

Nabłonek wielowarstwowy jako pośredni etap metaplazji

Istnieją dowody na istnienie rodzaju nabłonka znanego jako nabłonek wielowarstwowy, który wykazuje połączone cechy płaskie i walcowate, prawdopodobnie reprezentujące pośrednią fazę w reakcji metaplastycznej. Nabłonek wielowarstwowy jest silnie związany z refluksowym zapaleniem przełyku i wykazuje profil mucyny i cytokeratyny podobny do nabłonka walcowatego przełyku Barretta oraz czynników transkrypcyjnych jelitowych.¹

Skumulowane dowody wykazały, że metaplazja płasko-walcowata występuje we wczesnym pośrednim stadium charakteryzującym się obecnością nabłonka łączącego cechy płaskie i walcowate, jako nabłonek wielowarstwowy.¹

Czynniki ryzyka i predyspozycje do rozwoju przełyku Barretta

Oprócz klasycznych czynników ryzyka, takich jak refluks żołądkowo-przełykowy, płeć męska i rasa kaukaska, inne niedawno zidentyfikowane czynniki ryzyka przełyku Barretta obejmują otyłość, szczególnie otyłość centralną, zespół metaboliczny i obturacyjny bezdech senny.¹

Osoby z otyłością, z przełykiem Barretta lub bez niego, były badane w celu określenia genotypu IGF-1R. Stwierdzono, że otyli pacjenci z przełykiem Barretta mieli częściej pro-proliferacyjny genotyp IGF-1R niż ci bez przełyku Barretta lub GERD.¹

Odkryto również czynniki genetyczne, które przyczyniają się do rozwoju przełyku Barretta. Stwierdzono, że trzy geny są przede wszystkim odpowiedzialne za ten stan. Są to CTHRC1, ASCC1 i MSR1, zwane również genami predyspozycji, ponieważ nie powodują one faktycznie przełyku Barretta, chyba że w zmutowanej formie.¹²

Zaobserwowano odwrotną zależność między infekcją Helicobacter pylori a przełykiem Barretta w badaniach obserwacyjnych, ale istnieje znaczna heterogenność między badaniami. Mechanizm, za pomocą którego H. pylori zapewnia ochronę przed przełykiem Barretta, nie jest jasny. Niektórzy badacze uważają, że bakterie mogą faktycznie sprawić, że zawartość żołądka będzie mniej szkodliwa dla przełyku, gdy występuje GERD.¹²

Progresja przełyku Barretta do gruczolakoraka

Chociaż przełyk Barretta jest najważniejszym czynnikiem ryzyka rozwoju gruczolakoraka przełyku, szacowane ryzyko progresji z przełyku Barretta do gruczolakoraka wynosi tylko 0,12% rocznie.¹

Przełyk Barretta zwiększa ryzyko raka przełyku 30-125 razy. Ryzyko rozwoju gruczolakoraka zależy od stopnia dysplazji histologicznej, ale może wynosić około 1% rocznie (zakres 0,1-2%), a ryzyko bezwzględne jest niskie.¹²

Złośliwa transformacja przełyku Barretta jest procesem dynamicznym, a każdy etap histopatologiczny od NDBE (przełyk Barretta bez dysplazji) do LGD (dysplazja niskiego stopnia), HGD (dysplazja wysokiego stopnia) i gruczolakoraka przełyku wiąże się z coraz poważniejszymi zmianami patologicznymi.¹

Jednocześnie z proliferacją i replikacją komórek przełyku w przełyku Barretta i związanej z nim neoplazji, proces apoptozy jest hamowany, a te zmiany w strukturze tkanki przełyku tworzą mikrośrodowisko guza i wyzwalają odpowiedź immunologiczną, co z kolei indukuje zmiany w biomarkerach komórek przełyku.¹

Biomarkery predykcyjne progresji

Rzeczywiście, szereg biomarkerów potencjalnie przewidujących wczesną obecność i progresję neoplazji związanej z przełykiem Barretta został zbadany, w tym:

p53 – jeden z najbardziej badanych białek¹
Cyklina A – uważana za wiarygodny biomarker predykcyjny progresji neoplastycznej¹
cMYC – część rodziny genów MYC promujących proliferację komórek, która może przyspieszyć tworzenie raka¹
Ki-67 – białko jądrowe związane z proliferacją komórkową¹
Ekspresja mikroRNA – zmiany w regulacji podczas złośliwej transformacji przełyku Barretta¹
lncRNA SPRY4-IT1, TUG1, POU3F3, HNF1A-AS1 i MALAT1 – zaproponowane jako wskaźniki progresji neoplastycznej u pacjentów z przełykiem Barretta¹
Aktywność telomerazy – ściśle związana z przeżyciem komórek nowotworowych, a aktywność telomerazy wzrasta wraz z rozwojem dysplazji¹

Wpływ leczenia na progresję przełyku Barretta

Leczenie przełyku Barretta ma na celu zmniejszenie refluksu kwasu do przełyku. Chociaż GERD jest głównym czynnikiem ryzyka rozwoju gruczolakoraka przełyku, nie jest jasne, czy GERD predysponuje pacjentów do nowotworów złośliwych poprzez powodowanie przełyku Barretta, czy poprzez wpływ na karcynogenezę u pacjentów z już ustalonym przełykiem Barretta.¹

Prowokacyjne wyniki retrospektywnej analizy sugerują, że terapia inhibitorami pompy protonowej (PPI) może zmieniać progresję przełyku Barretta do dysplazji i podkreśla rolę supresji kwasu w leczeniu pacjentów z przełykiem Barretta.¹

Ablacja nabłonka Barretta ma na celu zniszczenie nabłonka Barretta na wystarczającą głębokość, aby wyeliminować metaplazję jelitową i umożliwić ponowny wzrost nabłonka płaskiego.¹

Mechanizm uszkodzenia przy krioablacji jest unikalny w porównaniu z innymi technikami ablacyjnymi. Krioablacja indukuje apoptozę, powoduje krionekrozę w temperaturach superchłodnych (-76°C do -196°C), powoduje przejściowe niedokrwienie i może powodować stymulację immunologiczną. Nabłonek Barretta jest odporny na apoptozę i dlatego może być wyjątkowo odpowiedni do leczenia krioablacją.¹

Jeśli usunie się dotknięte obszary i zatrzyma to, co powodowało uszkodzenie przełyku, przełyk Barretta może zostać wyleczony. Ale może powrócić. Czasami warstwa metaplazji ukrywa się pod warstwą nowej, normalnej tkanki. Czasami uraz trwa i tak proces metaplazji trwa nadal.¹

Aktualne zrozumienie patogenezy przełyku Barretta

Pomimo że przełyk Barretta jest znany od ponad 50 lat, szczegóły jego patogenezy wciąż nie są jasne. Stwierdzono, że szereg szlaków sygnalizacyjnych rozwojowych i czynników transkrypcyjnych ma kluczowe znaczenie dla spowodowania, że dojrzały nabłonek płaski zmienia się w komórki walcowate (transróżnicowanie) lub powodowania, że niedojrzałe komórki progenitorowe przełyku przechodzą różnicowanie walcowate, a nie płaskie (transprzekierowanie).¹

Obecne koncepcje patogenezy przełyku Barretta sugerują, że jest to złożony proces wieloetapowy, w którym istotną rolę odgrywają:

Przewlekłe zapalenie przełyku wywołane refluksem treści żołądkowej¹²
Aktywacja szlaków sygnałowych, takich jak NF-κB, Notch, Hedgehog, BMP i Wnt¹²
Zmiany w ekspresji czynników transkrypcyjnych, szczególnie CDX2¹²
Przeprogramowanie komórek macierzystych przełyku¹²
Pośrednie etapy metaplazji, w tym nabłonek wielowarstwowy¹²
Zmiany genetyczne i epigenetyczne prowadzące do niestabilności genomowej¹

Lepsze zrozumienie patogenezy przełyku Barretta, w połączeniu z rozwojem nieinwazyjnych narzędzi oceny ryzyka, miejmy nadzieję, doprowadzi do bardziej ukierunkowanych i skutecznych nieinwazyjnych programów badań przesiewowych w dobrze zdefiniowanej populacji.¹ Potrzebne są dalsze badania w celu pełnego zrozumienia mechanizmu patogenezy przełyku Barretta.¹

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Materiały źródłowe

#1 Barrett Esophagus – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK430979/
Barrett esophagus is a premalignant condition partly related to esophageal reflux, characterized by gastric and, more importantly, intestinal columnar metaplasia of the normally squamous mucosa of the distal esophagus. […] The exact pathogenesis of Barrett esophagus remains to be elucidated; however, it is believed to be a response to long-standing GERD. Some progress has been made in determining the molecular alterations and primary cell types involved. Study results have indicated that exposure to acid induces the squamous epithelial cells to secrete inflammatory cytokines such as interleukin 8 and interleukin 1b, which act to mediate the inflammatory response and signal T lymphocytes and neutrophils to migrate into the epithelium. Bile acids, specifically, have been shown to upregulate CDX2, the intestinal differentiation factor, and MUC2, the goblet cell-specific gene, within normal columnar and esophageal cancer cell lines.
#1 Pathophysiology and treatment of Barrettâs esophagus
https://pmc.ncbi.nlm.nih.gov/articles/PMC2921087/
Gastroesophageal reflux disease (GERD) affects an estimated 20% of the population in the United States. About 10%-15% of patients with GERD develop Barretts esophagus, which can progress to adenocarcinoma, currently the most prevalent type of esophageal cancer. The esophagus is normally lined by squamous mucosa, therefore, it is clear that for adenocarcinoma to develop, there must be a sequence of events that result in transformation of the normal squamous mucosa into columnar epithelium. This sequence begins with gastroesophageal reflux, and with continued injury metaplastic columnar epithelium develops. This article reviews the pathophysiology of Barretts esophagus and implications for its treatment. The effect of medical and surgical therapy of Barretts esophagus is compared. […] The development of Barretts esophagus is likely a two-step process. The first step involves the transformation of normal esophageal squamous mucosa to a simple columnar epithelium called cardiac mucosa. This occurs in response to chronic injury produced by repetitive episodes of gastric juice refluxing onto the squamous mucosa. The change from squamous to cardiac mucosa likely occurs relatively quickly, within a few years, while the second step, the development of goblet cells indicative of intestinal metaplasia, proceeds slowly, probably over 5-10 years. Once present, Barretts esophagus can progress to low- and high-grade dysplasia, and ultimately to adenocarcinoma. This entire process is commonly described as the Barretts metaplasia-dysplasia-carcinoma sequence.
#1 Pathophysiology and treatment of Barrettâs esophagus
https://pmc.ncbi.nlm.nih.gov/articles/PMC2921087/
The precise details of the molecular mechanism by which squamous mucosa is transformed into cardiac mucosa remain unknown. However, there is likely to be a crucial interaction between normally sequestered esophageal stem cells and an intraluminal stimulus that drives this metaplastic process. Tobey et al have demonstrated that exposure of esophageal squamous mucosa to gastric juice produces dilated intercellular spaces that allow molecules of up to 20 kDa to permeate down to the stem cells in the basal layer. […] The development of goblet cells marks the transformation of cardiac mucosa into intestinal metaplasia. When an endoscopically visible length of this mucosa is present in the esophagus, the definition of Barretts esophagus has been met. While gastroesophageal reflux is known to be the primary factor responsible for the development of Barretts esophagus, the specific cellular events that lead to the transformation of cardiac mucosa into intestinalized cardiac mucosa are unknown. However, evidence is accumulating that intestinalization requires a specific condition or stimulus, and that Barretts esophagus occurs in a stepwise process.
#1 Pathophysiology and treatment of Barrettâs esophagus
https://pmc.ncbi.nlm.nih.gov/articles/PMC2921087/
It has been hypothesized that the mechanism by which acid and bile interact to cause Barretts esophagus is related to the ionized state of bile salts. It appears that in a weakly acidic environment certain bile acids are particularly toxic. At pH 3-6, these bile salts are soluble and non-ionized, and can enter mucosal cells, accumulate, and cause direct cellular injury. […] The molecular mechanisms by which cardiac mucosa acquires goblet cells remain to be elucidated. However, there is increasing evidence that expression of the homeobox gene Cdx-2 plays a pivotal role. The expression of this gene increases with progression from squamous mucosa with esophagitis to cardiac mucosa, and is maximal in the setting of intestinal metaplasia.
#1 Signaling Pathways in the Pathogenesis of Barrettâs Esophagus and Esophageal Adenocarcinoma
https://www.mdpi.com/1422-0067/24/11/9304
The multiple signaling pathways involved in BE are activated in epithelial cells, thus eliciting epithelialâstromal interactions. Inside epithelial cells in the distal esophagus, bile acids cause injury to organelles, including the mitochondrial membranes, thus triggering uncontrolled generation of reactive oxygen species, oxidative stress and DNA damage. […] Therefore, the development of intestinal metaplasia is an adaptational mechanism in the distal esophagus. Simultaneously, repeated reflux exposure, DNA injury, including TP53, and the accumulation of multiple mutations and genomic instability, drive the formation of dysplasia and EAC. […] The development of intestinal metaplasia in the distal esophagus is a complex multiple-stage process determined by the activity of several complementary signaling pathways, including epithelialâstromal interactions. This process does not involve mature epithelial cells, but instead involves SCs and progenitor cells, which give rise to several cell populations. Clonal evolution of these cell lineages leads to the development of BE.
#1 Signaling Pathways in the Pathogenesis of Barrettâs Esophagus and Esophageal Adenocarcinoma
https://www.mdpi.com/1422-0067/24/11/9304
Barrett’s esophagus (BE) is a premalignant lesion that can develop into esophageal adenocarcinoma (EAC). The development of Barrett’s esophagus is caused by biliary reflux, which causes extensive mutagenesis in the stem cells of the epithelium in the distal esophagus and gastro-esophageal junction. […] The classical concept of healing a caustic lesion has been replaced by the concept of a cytokine storm, which forms an inflammatory microenvironment eliciting a phenotypic shift toward intestinal metaplasia of the distal esophagus. This review describes the roles of the NOTCH, hedgehog, NF-ÎºB and IL6/STAT3 molecular pathways in the pathogenesis of BE and EAC. […] Two major hypotheses exist regarding the source of BE: the classical mechanism of healing a caustic injury and a phenotypic shift in the context of a so-called cytokine storm. These hypotheses are not mutually exclusive and can accompany each other, thereby leading to the reprogramming of stem cells (SCs) and subsequent changes in the architecture of the esophageal mucosa.
#1 Signaling Pathways in the Pathogenesis of Barrettâs Esophagus and Esophageal Adenocarcinoma
https://www.mdpi.com/1422-0067/24/11/9304
NF-ÎºB activation in the distal esophagus not only leads to persistent inflammation but also induces the development of intestinal metaplasia via the activation of CDX2, which is crucial for intestinal differentiation. […] The levels of IL-8 and IL-1Î² rise from erosive esophagitis to BE, and from BE to EAC, and levels of NF-ÎºB simultaneously increase, thus leading to epithelial cell proliferation, prevention of apoptosis and promotion of carcinogenesis. […] Repeated bile acid exposure in an acidic pH causes oxidative stress in squamous and metaplastic epithelia in BE, thereby leading to DNA damage, particularly double-strand breaks. […] The mutational load in BE without dysplasia varies widely and has been estimated to be 0.42â1.28 mutations per Mb, or higher. The mutational load increases in the following conditions, from lowest to highest: BE without dysplasia, low-grade dysplasia, high-grade dysplasia, and EAC. […] These data provide evidence that genomic catastrophe is important in malignant transformation in BE, thus serving as an alternative mechanism of carcinogenesis. The genomic catastrophe frequently observed in high-grade dysplasia and EAC is likely to explain the rapid neoplastic progression in BE.
#1 Signaling Pathways in the Pathogenesis of Barrettâs Esophagus and Esophageal Adenocarcinoma
https://www.mdpi.com/1422-0067/24/11/9304
The most established hypothesis of the origin of BE is the transcommitment of multipotent SCs and progenitor cells. However, different progenitor cells might reasonably be involved in the pathogenesis of BE and might be responsible for all cellular phenotypes of columnar metaplasia, thereby explaining the heterogeneity and the polyclonal and mosaic-like spread of metaplastic glands. […] The concept of reflux-induced, cytokine-mediated injury of the mucosa in the distal esophagus was proposed by Souza R.F. et al., who found that in rats with esophagoduodenostomy, ulcers appeared several weeks after the operation and thus were not initiated directly by acid and bile reflux via caustic injury. […] Bile acid exposure in the presence of acidic pH increases reactive oxygen species in keratinocytes and the metaplastic epithelium in BE, thereby leading to HIF-2Î± stabilization, nuclear translocation, binding to HIF-responsive elements, and the triggering of the synthesis and release of proinflammatory cytokines.
#1 Molecular Pathogenesis of Barrett Esophagus | Abdominal Key
https://abdominalkey.com/molecular-pathogenesis-of-barrett-esophagus/
Important progress recently has been made in understanding the underlying molecular mechanisms in the process of Barrett metaplasia. The current hypothesis is that the stepwise development of intestinal metaplasia is based on the upregulation of diverse signaling pathways involving SHH, WNTs, Notch, retinoic acid (RA), and bone morphogenetic protein (BMP), which normally are involved in development and homeostasis of the gut and other organs. […] The current concept of esophageal metaplasia is that chronic (inflammatory) injury caused by bile and acid reflux as seen in gastroesophageal reflux disease has led to the upregulation or renewed expression of the SHH-BMP4 signaling pathway, which changes the epithelial environment in favor of columnar cells or drives cells toward a columnar phenotype.
#1 Molecular Pathogenesis of Barrett Esophagus | Abdominal Key
https://abdominalkey.com/molecular-pathogenesis-of-barrett-esophagus/
In Barrett biopsies SHH and its receptor PTCH are increased. Also BMP4 and its downstream target pSMAD are highly expressed, whereas the expression of Noggin, its natural inhibitor, is low. […] In a surgical mouse model it was shown that CDX2 and MUC2 expression are late events in columnar cells, which already have upregulated BMP4-pSMAD pathway.
#1 Pathogenesis of Barrett s Esophagus | OMICS International
https://www.omicsonline.org/open-access/pathogenesis-of-barrett-s-esophagus-2161-069X-1000417.php?aid=72233
The Notch signaling pathway acts as a fundamental molecular signaling system that controls cell-fate decisions such as differentiation, proliferation, and apoptosis in almost all tissue types. […] Recent findings revealed a correlationship between the Notch signalling and CDX2 expression. […] It has been found that bile acid inhibition of Notch signaling in esophageal cells is correlated with an increase in Hath1 and CDX2 and may be one of the key processes contributing to the formation of BE. […] Previous study indicated that the BMP pathway may play a role in the transformation of esophageal squamous cells into columnar cells. […] Our results suggested that BMP4 mediates reflux-induced metaplastic transformation of inflamed esophageal squamous mucosa to columnar mucosa. […] Cumulative evidence showed that the squamous-to-columnar metaplasia occurs in an early intermediate stage characterized by the presence of epithelium combined squamous and columnar features, as multilayered epithelium.
#1
https://link.springer.com/article/10.1007/s00535-017-1342-1
In support of a molecular reprogramming process of squamous esophageal progenitor cells, immortalized esophageal squamous cell lines and tissues exposed to acid and bile salts in vitro or GERD in vivo increase their expression of the columnar transcription factors SOX9 and forkhead box protein A2 (FOXA2), which are targets of the Hedgehog pathway, and of the intestinal transcription factor caudal-related homeobox transcription factor 2 (Cdx2), a target of the (NF-B) pathway. […] These findings suggest that the generation of NO by gastroesophageal reflux could initiate reprogramming of progenitors in the esophagus by inhibiting Akt signaling causing reduction in SOX2, by decreasing the TA and NP isoforms of p63, and by upregulating CDX2, events that might lead to the development of the intestinal metaplasia of Barretts esophagus.
#1 Barrett Esophagus – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK430979/
Up to 90% of affected patients have a detectable clonal aberration of the p16 tumor suppressor gene. CDX2 and TP53 mutations are early molecular alterations found in metaplastic columnar epithelium even before morphologic dysplasia is recognized. However, immunohistochemical staining to evaluate these markers is not currently recommended in routine diagnostic cases of Barrett esophagus. […] There is evidence of a type of epithelium known as multilayered epithelium, which shows combined squamous and columnar features, likely representing an intermediate phase within the metaplastic reaction. The multilayered epithelium is strongly associated with reflux esophagitis and expresses a mucin and cytokeratin profile similar to Barrett esophagus columnar epithelium and intestinal transcription factors. Further studies are needed to understand the complete mechanism of pathogenesis.
#1 Pathogenesis of Barrett s Esophagus | OMICS International
https://www.omicsonline.org/open-access/pathogenesis-of-barrett-s-esophagus-2161-069X-1000417.php?aid=72233
Several theories attempt to explain the cellular origins of BE, and all these hypotheses were based on experimental and clinical evidences. […] The promising cell source of BE was the migrating epithelium of gastric cardia, which repairing gastroesophageal reflux-mediated damage to the adjacent esophageal epithelium. […] At present, it is believed that BE develops de novo from cells intrinsic to the esophagus rather than migrating from the stomach. […] Many reports suggested that the gastric acid and bile reflux mixture activate the esophageal stem cell to transform the intestine-type columnar epithelium. […] The candidate stem cells in the esophagus include stem cells contained in the duct epithelium of the superficial cardia glands, or submucosal glands of the esophagus. […] However, the theory of submucosal glands has been called into question since BE developed in rat models where there are no submucosal glands, suggesting additional alternative mechanisms of BE occurrence.
#1 Pathogenesis of Barrett s Esophagus | OMICS International
https://www.omicsonline.org/open-access/pathogenesis-of-barrett-s-esophagus-2161-069X-1000417.php?aid=72233
It has been confirmed that GERD mainly induced alterations of the expression of important developmental transcription factors, which causing esophageal squamous cells switch to columnar cells (transdifferentiation) or causing immature esophageal progenitor cells to undergo columnar rather than squamous differentiation (transcommitment). […] The altered basal stem cell differentiation could be because of direct toxicity of the refluxate. […] The stem cell theory is attractive, as it explains the variety of cellular phenotypes found in Barretts esophagus, as well as how regeneration of basal stem cell is possible, and it correlates well with origin of cell intrinsic to the esophagus. […] The precise molecular mechanism of Barretts metaplasia remains unknown. […] Several signaling pathways, including Wnt, BMP, Klf4, NFB, Notch and sonic Hedgehog, and downstream transcription factors have been shown to play a fundamental role driving the formation of BE in the setting of GERD.
#1 Recent developments in pathogenesis, diagnosis and therapy of Barrett’s esophagus
https://www.wjgnet.com/1007-9327/full/v21/i21/6479.htm
Recent developments in pathogenesis, diagnosis and therapy of Barrett’s esophagus. […] This review examines recent updates in the pathogenesis of BE and comprehensively discusses known risk factors. […] New developments in the understanding of BE pathogenesis, screening, the neoplastic potential of BE, along with improvements in endoscopic therapeutic options, imaging techniques and molecular markers may impact future EAC mortality. […] In addition to the classic risk factors of gastroesophageal reflux, male gender and Caucasian race, other BE risk factors recently identified include obesity, specifically central obesity, metabolic syndrome, and obstructive sleep apnea. […] The exact molecular mechanisms by which central obesity promotes replacement of injured squamous epithelium with columnar metaplasia are the focus of intense research.
#1 Azthena logo with the word Azthena
https://www.news-medical.net/health/Barretts-Esophagus-Genetics.aspx
Mutations of this gene locus are associated with Barretts esophagus and esophageal adenocarcinoma. They may act as negative regulators of the collagen matrix homeostasis. […] The mechanism of obesity in the development of BE is not clearly defined, but it is found to increase the risk of GERD. Obesity-induced increases in signaling through certain insulin-like growth factor pathways which favor proliferation, and through insulin pathways, may be involved as well in the etiology of BE. […] Patients with obesity, either with or without BE, have been studied to determine the IGF-1R genotype. It was found that obese patients with BE had the pro-proliferative IGF-1R genotype more commonly than those without BE or GERD.
#1 Azthena logo with the word Azthena
https://www.news-medical.net/health/Barretts-Esophagus-Genetics.aspx
Although epidemiologic studies point to environmental factors, obesity, smoking, esophageal reflux, and diet as the main causes of Barretts esophagus (BE), there is growing evidence of a genetic predisposition as well. It is now fairly clear that the role of genetics is greatest in the initial stages of the disease. […] A number of research studies on this subject have concluded that three genes are primarily responsible for this condition. These genes are thought to play a vital role in increasing the risk of Barretts esophagus following their transformation or mutation. These are CTHRC1, ASCC1, and MSR1, also called the predisposition genes, as they do not actually cause Barretts esophagus unless in mutated form. […] The germline mutations in the predisposition genes cause the progress of esophageal disorders. Also, the mutations in the MSR1, CTHRC1, and ASCC1 genes are associated with BE and esophageal adenocarcinoma (p0.001). BE is typically identified only in the terminal phase, which endangers the patient severely. Esophageal carcinomas arise from the pre-existing condition of BE, which in turn develops as a result of chronic gastroesophageal reflux which produces chronic inflammation.
#1 Recent developments in pathogenesis, diagnosis and therapy of Barrett’s esophagus
https://www.wjgnet.com/1007-9327/full/v21/i21/6479.htm
Genetic factors which contribute to BE have also been discovered. […] An inverse relationship between Helicobacter pylori and BE has been noted in observational studies, but significant heterogeneity between studies exists. […] New insights into BE pathogenesis, coupled with the development of non-invasive risk assessment tools will hopefully lead to more focused and effective non-invasive screening programs in a well-defined population.
#1 Diagnostic and predictive biomarkers for Barrettâs esophagus: a narrative review – Di – Digestive Medicine Research
https://dmr.amegroups.org/article/view/7106/html
Barretts esophagus (BE) is a metaplastic alteration that squamous epithelial cells being replaced by columnar epithelium with goblet cells, and is well established as the precursor lesion for esophageal adenocarcinoma (EAC). […] The malignant transformation of BE is a dynamic process, with each histopathologic stage from NDBE to LGD, HGD, and EAC accompanied by increasingly severe pathological alterations. […] Concurrent with the proliferation and replication of the esophageal cells in BE and its related neoplasia, the process of apoptosis is inhibited, and these alterations in the structure of esophageal tissue establish a tumor microenvironment, and trigger an immune response, which in turn induce changes in the biomarkers of the esophageal cells. […] Although BE is the most important risk factor for the development of EAC, the estimated risk of progression from BE to EAC is only 0.12% per annum.
#1 Barrettâs Esophagus | Memorial Sloan Kettering Cancer Center
https://www.mskcc.org/cancer-care/types/esophageal/risk-factors/barrett-s-esophagus
After someone has had gastroesophageal reflux disease (GERD) for many years, it can advance to Barretts esophagus. Barretts is a way the esophagus defends itself: The cells in the lining of the esophagus start to change because theyve been exposed to acid for many years. Barretts esophagus is considered a precancerous lesion and increases the risk for esophageal cancer. […] But Barretts esophagus increases the risk of esophageal cancer by 125 times. […] Doctors use a technique called endoscopy to diagnose and stage Barretts esophagus. […] If the doctor sees the kind of changes that signal Barretts esophagus, she or he will take a tissue sample by passing special instruments through the endoscope. […] One of our experts will look at the biopsy under a microscope for the kind of cell changes that come with cancer. This will help us determine how far along the Barretts esophagus is, and whether it has become cancerous and could spread to other areas of the body.
#1 Diagnostic and predictive biomarkers for Barrettâs esophagus: a narrative review – Di – Digestive Medicine Research
https://dmr.amegroups.org/article/view/7106/html
Indeed, a number of biomarkers with the potential to predict the early presence and progression of Barretts related neoplasia have been studied, and these will be discussed further below. […] p53 is one of the most studied proteins. […] Cyclin A has also been considered as a reliable predictive biomarker for neoplastic progression. […] cMYC is part of the cell proliferation promoting MYC gene family, and therefore can accelerate cancer formation. […] Research has confirmed that increased expression of cMYC runs through the spectrum of neoplastic progression of BE, from NDBE, to LGD, HGD, and EAC. […] Ki-67 is a nuclear protein that is associated with cellular proliferation. […] During the malignant transformation of BE, microRNA expression appeared to be up-regulated or down-regulated.
#1 Diagnostic and predictive biomarkers for Barrettâs esophagus: a narrative review – Di – Digestive Medicine Research
https://dmr.amegroups.org/article/view/7106/html
In addition to microRNA, lncRNA SPRY4-IT1, TUG1, POU3F3, HNF1A-AS1, and MALAT1 have also been proposed to indicate the neoplastic progression in BE patients. […] It has been shown that activated telomerase is closely related to the survival of tumor cells, and the activity of telomerase increases with the development of dysplasia.
#1 Barrettâs Esophagus | AAFP
https://www.aafp.org/pubs/afp/issues/2004/0501/p2113.html
Treatment of Barretts esophagus is aimed at decreasing reflux of acid into the esophagus. Although GERD is the primary risk factor for developing esophageal adenocarcinoma, it is unclear whether GERD predisposes patients to malignancy by causing Barretts esophagus or by affecting carcinogenesis in patients with established Barretts esophagus. […] Barretts esophagus is an acquired condition that results from injury of the squamous epithelium of the esophagus through repetitive exposure to gastric acid.
#1 Barrett’s Esophagus: Diagnosis and Treatment
https://www.medscape.org/viewarticle/463423
This study shows that the endoscopic appearance and extent of HGD in BE can predict the presence of cancer at esophagectomy. […] 17p (p53) LOH (loss of heterozygosity) predicts progression of BE to cancer. […] These provocative results from a retrospective analysis raise the possibility that PPI therapy may alter the progression of BE to dysplasia, and emphasizes the role of acid suppression in the treatment of patients with BE. […] New forms of endoscopic therapy, such as mucosal resection and cryotherapy, are being evaluated and, although promising, can be associated with complications including stricture formation.
#1 Barrett Esophagus Treatment & Management: Approach Considerations, Barrett Esophagus Screening and Surveillance, Ablative Therapy for Barrett Esophagus
https://emedicine.medscape.com/article/171002-treatment
In addition to acid, the reflux of pancreatic and biliary secretions into the esophagus has been implicated in the pathogenesis of Barrett esophagus. […] However, while studies have shown surgery to be efficacious in the control of GERD symptoms, the results regarding Barrett esophagus regression are inconclusive. No good evidence indicates that surgical therapy provides regression in Barrett esophagus. […] With relation to reduction of cancer risk in Barrett esophagus, evidence remains insufficient to recommend surgery over medical therapy, although regression of features associated with cancer risk appears to be more common following surgical intervention than medical therapy. […] The goal of ablative therapy is to destroy the Barrett epithelium to a sufficient depth to eliminate the intestinal metaplasia and allow regrowth of squamous epithelium.
#1 Barrett Esophagus Treatment & Management: Approach Considerations, Barrett Esophagus Screening and Surveillance, Ablative Therapy for Barrett Esophagus
https://emedicine.medscape.com/article/171002-treatment
The mechanism of injury is unique relative to other ablative techniques. Cryoablation induces apoptosis, causes cryonecrosis at supercold temperatures (-76C to -196C), results in transient ischemia, and can cause immune stimulation. The Barrett epithelium is resistant to apoptosis and, therefore, may be uniquely suited for treatment by cryoablation.
#1 Barrettâs Esophagus: Symptoms, Causes, Treatments & Medications
https://my.clevelandclinic.org/health/diseases/14432-barretts-esophagus
If you remove the affected tissue and stop whatever was injuring your esophagus, Barretts esophagus may be cured. But it can return. Sometimes, a layer of metaplasia hides underneath a layer of new, normal tissue. Sometimes, the injury continues, and so the process of metaplasia continues. […] Barretts esophagus by itself wont harm you. But its an important sign of prior injury. Its also a mild warning of possible future harm. What it means is that you need to address the underlying cause of injury to your esophagus.
#1 Pathogenesis of Barrett s Esophagus | OMICS International
https://www.omicsonline.org/open-access/pathogenesis-of-barrett-s-esophagus-2161-069X-1000417.php?aid=72233
Although BE has been known for over 50 years, the details of its pathogenesis are still unclear. […] It has been reported that a number of developmental signalling pathways and transcription factors are critically important for causing mature squamous epithelium to change into columnar cells (transdifferentiation) or causing immature esophageal progenitor cells to undergo columnar rather than squamous differentiation (transcommitment).
#1 Molecular Pathogenesis of Barrett Esophagus | Abdominal Key
https://abdominalkey.com/molecular-pathogenesis-of-barrett-esophagus/
This article focuses on recent findings on the molecular mechanisms involved in esophageal columnar metaplasia. Signaling pathways and their downstream targets activate specific transcription factors leading to the expression of columnar and the more specific intestinal-type of genes, which gives rise to Barrett metaplasia. […] At present, the SHH-BMP4/pSMAD pathway, its antagonists, and downstream targets seem to be the important signaling pathways involved in the development of earliest stages of columnar metaplasia. […] SHH-BMP4/pSMAD signaling is crucial for the induction of columnar genes leading to the nonintestinal-type of columnar metaplasia. […] Expression of the intestine-specific genes as seen in the later stage of the intestinal-type of Barrett metaplasia seems to be mediated by a pSMAD-CDX2 interaction, Wnt, and Notch signaling.
#2 Pathophysiology and treatment of Barrettâs esophagus
https://pmc.ncbi.nlm.nih.gov/articles/PMC2921087/
Gastroesophageal reflux disease (GERD) affects an estimated 20% of the population in the United States. About 10%-15% of patients with GERD develop Barretts esophagus, which can progress to adenocarcinoma, currently the most prevalent type of esophageal cancer. The esophagus is normally lined by squamous mucosa, therefore, it is clear that for adenocarcinoma to develop, there must be a sequence of events that result in transformation of the normal squamous mucosa into columnar epithelium. This sequence begins with gastroesophageal reflux, and with continued injury metaplastic columnar epithelium develops. This article reviews the pathophysiology of Barretts esophagus and implications for its treatment. The effect of medical and surgical therapy of Barretts esophagus is compared. […] The development of Barretts esophagus is likely a two-step process. The first step involves the transformation of normal esophageal squamous mucosa to a simple columnar epithelium called cardiac mucosa. This occurs in response to chronic injury produced by repetitive episodes of gastric juice refluxing onto the squamous mucosa. The change from squamous to cardiac mucosa likely occurs relatively quickly, within a few years, while the second step, the development of goblet cells indicative of intestinal metaplasia, proceeds slowly, probably over 5-10 years. Once present, Barretts esophagus can progress to low- and high-grade dysplasia, and ultimately to adenocarcinoma. This entire process is commonly described as the Barretts metaplasia-dysplasia-carcinoma sequence.
#2 Barrettâs Esophagus: An Updated Review
https://www.mdpi.com/2075-4418/13/2/321
Barrett’s esophagus is believed to occur as a two-step process. The first step, which occurs relatively quickly over a period of a few years, involves transformation of normal esophageal squamous mucosa into a simple columnar epithelium which lacks parietal cells, known as cardiac mucosa. This initial transformation is a result of exposure from chronic repeated episodes of refluxing gastric acid onto the squamous mucosa. The presence of this initial transformation into a cardiac mucosa has been supported by objective markers of GERD, including incompetence of the lower esophageal sphincter (LES), increased acid exposure in the esophagus on 24-h pH monitoring, erosive esophagitis, and the presence of a hiatal hernia. The precise molecular mechanism for this change is still unknown; however, Tobey et al. had shown that chronic exposure of esophageal mucosa to gastric acid, had produced increased intercellular spaces which allow for hydrochloric acid molecules to permeate down to the stem cells in the basal layer and stimulate afferent nerves. The ability of gastric acid to permeate through, can be responsible for the sensation of heartburn and the phenotypic transformation to simple columnar epithelium.
#2 Treatment of Barrettâs esophagus: a narrative review – Nesheiwat – Annals of Esophagus
https://aoe.amegroups.org/article/view/6806/html
Barretts esophagus (BE) is an acquired condition through which most cases are secondary to the damaging effects of gastroesophageal reflux disease (GERD). Barretts esophagus is the only recognized premalignant lesion of esophageal adenocarcinoma (EAC) and it carries an 11-fold higher risk of EAC compared to the general population. This risk is dependent on the degree of dysplasia and therefore management focuses on treating the underlying GERD and varies based on the degree of dysplasia. […] The process of developing BE is said to occur in two steps. The first step occurs secondary to the reflux of both gastric fluid and duodenal secretions onto the squamous epithelium of the esophagus which transforms it into simple columnar epithelium, that of the cardiac mucosa. This chronic mucosal injury occurs over a span of a few years and involves an inflammatory cascade that stimulates cellular proliferation and genetic alterations that then induces genetic destabilization. The second step spans over 5 to 10 years and involves intestinal metaplasia via the development of goblet cells. Once BE is present, the development of low-grade dysplasia (LGD) to high-grade dysplasia (HGD) and eventually adenocarcinoma occurs through the metaplasia-dysplasia-carcinoma sequence.
#2 Barrett Esophagus Treatment & Management: Approach Considerations, Barrett Esophagus Screening and Surveillance, Ablative Therapy for Barrett Esophagus
https://emedicine.medscape.com/article/171002-treatment
In addition to acid, the reflux of pancreatic and biliary secretions into the esophagus has been implicated in the pathogenesis of Barrett esophagus. […] However, while studies have shown surgery to be efficacious in the control of GERD symptoms, the results regarding Barrett esophagus regression are inconclusive. No good evidence indicates that surgical therapy provides regression in Barrett esophagus. […] With relation to reduction of cancer risk in Barrett esophagus, evidence remains insufficient to recommend surgery over medical therapy, although regression of features associated with cancer risk appears to be more common following surgical intervention than medical therapy. […] The goal of ablative therapy is to destroy the Barrett epithelium to a sufficient depth to eliminate the intestinal metaplasia and allow regrowth of squamous epithelium.
#2
https://link.springer.com/article/10.1007/s00535-017-1342-1
Reflux esophagitis damages the squamous epithelium that normally lines the esophagus, and promotes replacement of the damaged squamous lining by the intestinal metaplasia of Barretts esophagus, the precursor of esophageal adenocarcinoma. […] Therefore, to prevent the development of Barretts metaplasia and esophageal adenocarcinoma, the pathogenesis of reflux esophagitis must be understood. […] We have reported that reflux esophagitis, both in a rat model and in humans, develops as a cytokine-mediated inflammatory injury (i.e., cytokine sizzle), not as a caustic chemical injury (i.e., acid burn), as traditionally has been assumed. […] Moreover, reflux induces activation of hypoxia inducible factor (HIF)-2, which enhances the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) causing increases in pro-inflammatory cytokines and in migration of T lymphocytes, an underlying molecular mechanism for this cytokine-mediated injury.
#2 Molecular Pathogenesis of Barrett Esophagus | Abdominal Key
https://abdominalkey.com/molecular-pathogenesis-of-barrett-esophagus-2/
Important progress recently has been made in understanding the underlying molecular mechanisms in the process of Barrett metaplasia. The current hypothesis is that the stepwise development of intestinal metaplasia is based on the upregulation of diverse signaling pathways involving SHH, WNTs, Notch, retinoic acid (RA), and bone morphogenetic protein (BMP), which normally are involved in development and homeostasis of the gut and other organs. […] The current concept of esophageal metaplasia is that chronic (inflammatory) injury caused by bile and acid reflux as seen in gastroesophageal reflux disease has led to the upregulation or renewed expression of the SHH-BMP4 signaling pathway, which changes the epithelial environment in favor of columnar cells or drives cells toward a columnar phenotype.
#2 Molecular Pathogenesis of Barrett Esophagus | Abdominal Key
https://abdominalkey.com/molecular-pathogenesis-of-barrett-esophagus-2/
In Barrett biopsies SHH and its receptor PTCH are increased. Also BMP4 and its downstream target pSMAD are highly expressed, whereas the expression of Noggin, its natural inhibitor, is low. […] In a surgical mouse model in which bile and acid reflux is induced through an esophagojejunostomy, pSMAD and BMP4 were found to be upregulated in the inflamed esophagus and the metaplastic glands.
#2 Another Notch in the mechanism of Barrett oesophagus progression | Nature Reviews Gastroenterology & Hepatology
https://www.nature.com/articles/s41575-020-0313-9
A new study has examined the mechanism of progression from Barrett oesophagus to oesophageal adenocarcinoma (EAC) in mouse and human tissues. This work showed an association between increased Notch signalling and decreased goblet cell density that could lead to new therapeutic strategies to prevent EAC in patients with Barrett oesophagus. […] Notch signalling is key in regulating LGR5+ stem cells of the intestinal epithelium and determining cell fate, and it is essential for proliferation and differentiation across the gastrointestinal tract. This process might be particularly relevant to Barrett oesophagus and progression to EAC as aberrant Notch signalling has been observed in histological specimens from patients with Barrett oesophagus as well as in a transgenic model of Barrett oesophagus (L2-IL1B mice).
#2 Azthena logo with the word Azthena
https://www.news-medical.net/health/Barretts-Esophagus-Genetics.aspx
Although epidemiologic studies point to environmental factors, obesity, smoking, esophageal reflux, and diet as the main causes of Barretts esophagus (BE), there is growing evidence of a genetic predisposition as well. It is now fairly clear that the role of genetics is greatest in the initial stages of the disease. […] A number of research studies on this subject have concluded that three genes are primarily responsible for this condition. These genes are thought to play a vital role in increasing the risk of Barretts esophagus following their transformation or mutation. These are CTHRC1, ASCC1, and MSR1, also called the predisposition genes, as they do not actually cause Barretts esophagus unless in mutated form. […] The germline mutations in the predisposition genes cause the progress of esophageal disorders. Also, the mutations in the MSR1, CTHRC1, and ASCC1 genes are associated with BE and esophageal adenocarcinoma (p0.001). BE is typically identified only in the terminal phase, which endangers the patient severely. Esophageal carcinomas arise from the pre-existing condition of BE, which in turn develops as a result of chronic gastroesophageal reflux which produces chronic inflammation.
#2 Pathogenesis of Barrett s Esophagus | OMICS International
https://www.omicsonline.org/open-access/pathogenesis-of-barrett-s-esophagus-2161-069X-1000417.php?aid=72233
Several theories attempt to explain the cellular origins of BE, and all these hypotheses were based on experimental and clinical evidences. […] The promising cell source of BE was the migrating epithelium of gastric cardia, which repairing gastroesophageal reflux-mediated damage to the adjacent esophageal epithelium. […] At present, it is believed that BE develops de novo from cells intrinsic to the esophagus rather than migrating from the stomach. […] Many reports suggested that the gastric acid and bile reflux mixture activate the esophageal stem cell to transform the intestine-type columnar epithelium. […] The candidate stem cells in the esophagus include stem cells contained in the duct epithelium of the superficial cardia glands, or submucosal glands of the esophagus. […] However, the theory of submucosal glands has been called into question since BE developed in rat models where there are no submucosal glands, suggesting additional alternative mechanisms of BE occurrence.
#2
https://omim.org/entry/614266
A number sign (#) is used with this entry because rare germline mutations have been found in the MSR1 (153622), ASCC1 (614215), and CTHRC1 (610635) genes in patients with Barrett esophagus and/or esophageal adenocarcinoma. […] The main cause of Barrett metaplasia is gastroesophageal reflux (GER; 109350). The retrograde movement of acid and bile salts from the stomach into the esophagus in this disease causes prolonged injury to the esophageal epithelium and induces chronic esophagitis, which in turn is believed to trigger the pathologic changes (summary by Wong et al., 2005). […] In endoscopic tissue biopsies, Wong et al. (2005) found that CDX1 (600746) mRNA and protein were universally expressed in all samples of Barrett metaplasia (BM) tested but not in normal esophageal squamous or gastric body epithelia. They attributed this tissue-specific expression pattern to the methylation status of the CDX1 promoter, which was completely methylated in normal squamous and gastric epithelia but demethylated in a majority of DNA clones from BM tissue. Conjugated bile salts and the inflammatory cytokines TNF-alpha (191160) and IL1-beta (147720) increased CDX1 mRNA expression via the NFKB (see 164011) pathway in vitro, but only when the CDX1 promoter was unmethylated or partially methylated. Wong et al. (2005) suggested that CDX1 is the molecular link between the etiologic agents that cause BM and the induction of an intestinal phenotype, and that CDX1 promoter demethylation is the key trigger for the development of BM.
#2 Barrett’s Esophagus | MUSC Health | Charleston SC
https://muschealth.org/medical-services/ddc/patients/digestive-diseases/esophagus/barretts-esophagus
In some people, washback of acids will cause irritations or ulcerations of the esophagus. As a result, the esophagus tries to repair itself from inflammation or ulceration by repairing the original cell lining. In 12% of patients, this replacement lining will not be the original type found in the esophagus, but more like that of the stomach. […] The formation of a new lining similar to the stomach is known as Barrett’s esophagus. […] In some patients, heartburn does not go away, and over time the acids in the stomach damage the cells in the esophagus to the extent that they cannot repair themselves … and this can lead to Barrett’s esophagus. Between 510 percent of people with GERD end up developing this condition. […] H. pylori (or Helicobacter pylori) infection may decrease the risk of developing Barrett’s esophagus. The mechanism by which H. pylori provides protection from Barrett’s esophagus is unclear. Some researchers believe the bacteria can actually make the stomach contents less damaging to the esophagus when GERD is present.
#2 Barrett esophagus | Radiology Reference Article | Radiopaedia.org
https://radiopaedia.org/articles/barrett-oesophagus?lang=us
Barrett esophagus is a term for intestinal metaplasia of the esophagus. It is considered the precursor lesion for esophageal adenocarcinoma. […] Barrett esophagus represents progressive metaplasia of esophageal stratified squamous cell epithelium to columnar epithelium. Although the exact number varies, 90-100% of esophageal adenocarcinoma is thought to arise from this metaplasia. […] Although patients with Barrett esophagus have a 30x risk of developing esophageal adenocarcinoma, the annual risk of developing adenocarcinoma depends on the degree of histological dysplasia, but may be ~1% (range 0.1-2%), and the absolute risk is low.
#2 Barrett’s esophagus: Pathogenesis and malignant transformation – UpToDate
https://www.uptodate.com/contents/barretts-esophagus-pathogenesis-and-malignant-transformation/print
Barrett’s esophagus is the condition in which metaplastic columnar mucosa that predisposes to cancer development replaces the stratified squamous mucosa that normally lines the distal esophagus. The condition develops as a consequence of chronic gastroesophageal reflux disease and predisposes to the development of adenocarcinoma of the esophagus. […] This topic will review the pathogenesis of Barrett’s esophagus and the mechanisms of transformation into esophageal adenocarcinoma. […] Barrett’s esophagus results from chronic reflux esophagitis caused by the gastroesophageal reflux of acid and other noxious substances. […] Patients who have long-segment Barrett’s esophagus are predisposed to reflux caustic gastric contents (often without warning symptoms) into an esophagus whose ability to protect itself is compromised by defective clearance mechanisms and diminished secretion of growth factors.
#2 Pathogenesis of Barrett s Esophagus | OMICS International
https://www.omicsonline.org/open-access/pathogenesis-of-barrett-s-esophagus-2161-069X-1000417.php?aid=72233
It has been confirmed that GERD mainly induced alterations of the expression of important developmental transcription factors, which causing esophageal squamous cells switch to columnar cells (transdifferentiation) or causing immature esophageal progenitor cells to undergo columnar rather than squamous differentiation (transcommitment). […] The altered basal stem cell differentiation could be because of direct toxicity of the refluxate. […] The stem cell theory is attractive, as it explains the variety of cellular phenotypes found in Barretts esophagus, as well as how regeneration of basal stem cell is possible, and it correlates well with origin of cell intrinsic to the esophagus. […] The precise molecular mechanism of Barretts metaplasia remains unknown. […] Several signaling pathways, including Wnt, BMP, Klf4, NFB, Notch and sonic Hedgehog, and downstream transcription factors have been shown to play a fundamental role driving the formation of BE in the setting of GERD.
#2 Pathogenesis of Barrett s Esophagus | OMICS International
https://www.omicsonline.org/open-access/pathogenesis-of-barrett-s-esophagus-2161-069X-1000417.php?aid=72233
The Notch signaling pathway acts as a fundamental molecular signaling system that controls cell-fate decisions such as differentiation, proliferation, and apoptosis in almost all tissue types. […] Recent findings revealed a correlationship between the Notch signalling and CDX2 expression. […] It has been found that bile acid inhibition of Notch signaling in esophageal cells is correlated with an increase in Hath1 and CDX2 and may be one of the key processes contributing to the formation of BE. […] Previous study indicated that the BMP pathway may play a role in the transformation of esophageal squamous cells into columnar cells. […] Our results suggested that BMP4 mediates reflux-induced metaplastic transformation of inflamed esophageal squamous mucosa to columnar mucosa. […] Cumulative evidence showed that the squamous-to-columnar metaplasia occurs in an early intermediate stage characterized by the presence of epithelium combined squamous and columnar features, as multilayered epithelium.
#3 Barrett’s esophagus – Wikipedia
https://en.wikipedia.org/wiki/Barrett%27s_esophagus
Barrett’s esophagus is a condition in which there is an abnormal (metaplastic) change in the mucosal cells that line the lower part of the esophagus. The main cause of Barrett’s esophagus is tissue adaptation to chronic acid exposure caused by reflux from the stomach. Barrett’s esophagus occurs due to chronic inflammation. The main cause of chronic inflammation is gastroesophageal reflux disease, GERD (UK: GORD). In this disease, acidic stomach, bile, and small intestine and pancreatic contents cause damage to the cells of the lower esophagus. This gives an advantage to cells that are more resistant to these corrosive substances. In particular, HOXA13-expressing stem cells that are characterised by distal (intestinal) characteristics are able to outcompete the normal squamous cells. During episodes of reflux, bile acids enter the esophagus, and this may be an important factor in carcinogenesis. Individuals with GERD and BE are exposed to high concentrations of deoxycholic acid that has cytotoxic effects and can cause DNA damage. This mechanism also explains the selection of HER2/neu (also called ERBB2) and the overexpressing (lineage-addicted) cancer cells during the process of carcinogenesis. The presence of intestinal metaplasia in Barrett’s esophagus represents a marker for the progression of metaplasia towards dysplasia and eventually adenocarcinoma. This factor combined with two different immunohistochemical expression of p53, Her2 and p16 leads to two different genetic pathways that likely progress to dysplasia in Barrett’s esophagus.
#3 Treatment of Barrettâs esophagus: a narrative review – Nesheiwat – Annals of Esophagus
https://aoe.amegroups.org/article/view/6806/html
Barretts esophagus (BE) is an acquired condition through which most cases are secondary to the damaging effects of gastroesophageal reflux disease (GERD). Barretts esophagus is the only recognized premalignant lesion of esophageal adenocarcinoma (EAC) and it carries an 11-fold higher risk of EAC compared to the general population. This risk is dependent on the degree of dysplasia and therefore management focuses on treating the underlying GERD and varies based on the degree of dysplasia. […] The process of developing BE is said to occur in two steps. The first step occurs secondary to the reflux of both gastric fluid and duodenal secretions onto the squamous epithelium of the esophagus which transforms it into simple columnar epithelium, that of the cardiac mucosa. This chronic mucosal injury occurs over a span of a few years and involves an inflammatory cascade that stimulates cellular proliferation and genetic alterations that then induces genetic destabilization. The second step spans over 5 to 10 years and involves intestinal metaplasia via the development of goblet cells. Once BE is present, the development of low-grade dysplasia (LGD) to high-grade dysplasia (HGD) and eventually adenocarcinoma occurs through the metaplasia-dysplasia-carcinoma sequence.
#3 Barrett’s esophagus – what it is, methods of diagnosis, symptoms and treatment of Barrett’s esophagus
https://medconsonline.com/en/blog/barretts-esophagus
The disease passes through three stages. Metaplasia (benign changes) without dysplasia (malignization): no visible precancerous changes of cells in the esophageal mucosa. Low-grade dysplasia: cells show early precancerous changes that may lead to cancer. High-grade dysplasia: esophageal cells show a high degree of precancerous changes that are considered the last stage before esophageal adenocarcinoma.
#3 Treatment of Barrettâs esophagus: a narrative review – Nesheiwat – Annals of Esophagus
https://aoe.amegroups.org/article/view/6806/html
The damage that acid causes to the esophageal epithelium creates dilated intercellular spaces that causes an increase in the transepithelial permeability allowing for larger molecules to diffuse across. This exposes basal layer stem cells to reflux fluid that induces a cascade of events leading to cell edema and eventual cell death. Phenotypic transformation of squamous cells into columnar mucosal cells then occurs due to a combination of tissue reparative processes in the setting of an acidic environment. […] It is important to note that BE is the strongest predicting factor of EAC even though only a small percentage of patients with BE will develop cancer.