Zespół rakowiczy – Patofizjologia i mechanizm

Zespół rakowiczy
Patofizjologia i mechanizm

Zespół rakowiaka jest paraneoplastycznym zespołem wywołanym przez przerzutowe, wysokozróżnicowane nowotwory neuroendokrynne (NET) środkowej części przewodu pokarmowego, które poprzez przerzuty do wątroby umożliwiają uwalnianie biologicznie aktywnych amin i peptydów do krążenia systemowego, omijając metabolizm pierwszego przejścia. Kluczową rolę w patofizjologii odgrywa serotonina (5-HT), której biosynteza w guzach NET może sięgać nawet 70% tryptofanu, co prowadzi do objawów takich jak biegunka oraz zwłóknienie krezki. Podwyższone stężenia 5-HIAA w moczu korelują z rozwojem zwłóknienia i choroby serca w przebiegu zespołu rakowiaka (Carcinoid Heart Disease, CHD), która manifestuje się zwłóknieniem zastawek serca, głównie trójdzielnej i płucnej, prowadząc do ich niedomykalności i stenozy. Mechanizm sercowych powikłań wiąże się z aktywacją receptorów 5-HT2B i wzrostem ekspresji TGF-β1, co stymuluje fibrogenezę i proliferację miofibroblastów. Warto podkreślić, że lewa strona serca jest zwykle chroniona dzięki inaktywacji peptydów w płucach, a choroba lewostronnych zastawek występuje rzadko, głównie przy przeciekach prawo-lewych lub pierwotnym rakowiaku oskrzeli.

Patogeneza zespołu rakowiaka (Carcinoid syndrome)

Mechanizm powstawania zespołu rakowiaka
Substancje odpowiedzialne za objawy zespołu rakowiaka
Serotonina jako główny mediator zespołu rakowiaka
Mechanizm powstawania choroby serca w przebiegu zespołu rakowiaka
Mechanizm zwłóknień w zespole rakowiaka
Kryzys rakowiaka

Leczenie zespołu rakowiaka

Kolejne rozdziały

Patogeneza zespołu rakowiaka (Carcinoid syndrome)

Zespół rakowiaka (Carcinoid syndrome) to rzadkie schorzenie kliniczne wywołane przez przerzutowe, wysokozróżnicowane nowotwory neuroendokrynne (NET), które pierwotnie wywodzą się najczęściej ze środkowej części przewodu pokarmowego (midgut) i są związane z przerzutami do wątroby.¹² Zespół ten występuje u około 30-40% pacjentów z wysokozróżnicowanymi guzami neuroendokrynnymi i jest zespołem paraneoplastycznym związanym z wydzielaniem licznych czynników humoralnych.³⁴

Mechanizm powstawania zespołu rakowiaka

Zespół rakowiaka powstaje, gdy biologicznie aktywne aminy i peptydy uwalniane są do krążenia systemowego, omijając metabolizm pierwszego przejścia przez wątrobe. W warunkach prawidłowych wątroba inaktywuje te substancje, jednak przerzuty guzów neuroendokrynnych do wątroby umożliwiają przedostawanie się tych produktów do krążenia ogólnego, wywołując efekty ogólnoustrojowe.⁵⁶

Patofizjologia zespołu rakowiaka jest ściśle związana z lokalizacją guza pierwotnego. Kiedy guzy te rozprzestrzeniają się do wątroby, pacjenci zwykle zaczynają rozwijać zespół rakowiaka. Faktycznie, zespół ten rozwija się, gdy substancje wazoaktywne wytwarzane przez guz rakowiaka omijają degradację wątrobową i uzyskują dostęp do krążenia systemowego.⁷

Guz neuroendokrynny jelita cienkiego zazwyczaj nie powoduje zespołu rakowiaka, dopóki nie dojdzie do przerzutów do wątroby, ponieważ produkty metaboliczne uwalniane przez guz są szybko niszczone przez enzymy krwi i wątroby w krążeniu wrotnym.⁸⁹ Jednak przerzuty do wątroby uwalniają produkty metaboliczne przez żyły wątrobowe bezpośrednio do krążenia systemowego.¹⁰

Substancje odpowiedzialne za objawy zespołu rakowiaka

Nowotwory neuroendokrynne wydzielają około 40 rodzajów biologicznie aktywnych amin i peptydów, przy czym serotonina jest najważniejsza w zespole rakowiaka.¹¹¹² Zidentyfikowano ponad 40 substancji potencjalnie związanych z zespołem rakowiaka, jednak ich indywidualny wkład w wywołanie różnych objawów rakowiaka i powikłań, takich jak choroba serca w przebiegu zespołu rakowiaka (CHD), pozostaje niejasny. Substancje te obejmują serotoninę (5-HT), która wydaje się być głównym markerem związanym z zespołem, a także histaminę, kalikreinę, prostaglandyny i tachykininy.¹³¹⁴¹⁵

Mimo że zidentyfikowano wiele substancji potencjalnie związanych z zespołem rakowiaka, dowody z dostępnej literatury są wystarczające jedynie, aby zgodzić się co do roli serotoniny jako mediatora biegunki i zwłóknienia związanego z zespołem rakowiaka. Bezpośrednia rola tachykinin i pośrednia rola katecholamin w patogenezie zespołu rakowiaka jest sugerowana przez kilka badań. Obecnie nie ma wystarczających dowodów na powiązanie histaminy, bradykininy, kalikreiny, prostaglandyn lub motyliny z zespołem rakowiaka.¹⁶

Serotonina jako główny mediator zespołu rakowiaka

W warunkach prawidłowych tylko 1% tryptofanu z diety jest przekształcany w serotoninę, ale w guzach neuroendokrynnych może to być nawet 70%.¹⁷¹⁸¹⁹ Zwiększone ilości serotoniny prowadzą do zwiększonej motoryki przewodu pokarmowego i hipersekrecji, powodując biegunkę, jeden z głównych objawów zespołu rakowiaka.²⁰²¹

Biosynteza 5-HT jest katalizowana przez TPH (tryptofanhydroksylazę), której istnieją dwie izoformy: TPH-1, wyrażana w komórkach enterochromafinowych przewodu pokarmowego, i TPH-2, uważana za źródło puli neuroprzekaźnika 5-HT w ośrodkowym układzie nerwowym i głównie wyrażana w neuronach jądra szwu pnia mózgu i neuronach splotów mięśniowych w jelicie.²²

Większość serotoniny we krwi jest syntetyzowana przez TPH-1, która wyłoniła się jako możliwy cel terapeutyczny dla rozwoju specyficznych inhibitorów.²³ To podejście terapeutyczne znalazło zastosowanie w leczeniu zespołu rakowiaka za pomocą telotristatu etylu, inhibitora TPH, ograniczającego enzym w biosyntezie 5-HT.²⁴

Fizjologicznie serotonina powoduje rozszerzenie naczyń i może zwiększać krzepnięcie krwi poprzez stymulację agregacji płytek krwi, co może prowadzić do rozsianego wykrzepiania wewnątrznaczyniowego (DIC); jednak serotonina jest przekształcana w 5-HIAA w organizmie.²⁵

Serotonina wydzielana przez NET odgrywa centralną rolę w zwłóknieniu krezki. Niedawne badanie wykazało istotny związek zwłóknienia krezki z podwyższonym poziomem 5-HIAA w moczu, sugerując potencjalny związek przyczynowy.²⁶²⁷ Inne badanie z udziałem 52 pacjentów z NET środkowej części przewodu pokarmowego wykazało, że podwyższony poziom serotoniny w płytkach krwi jest związany z obecnością masy w krezce.²⁸

Mechanizm powstawania choroby serca w przebiegu zespołu rakowiaka

Choroba serca w przebiegu zespołu rakowiaka (Carcinoid Heart Disease, CHD), znana również jako zespół Hedingera, jest znanym powikłaniem nowotworów neuroendokrynnych i występuje szczególnie często u pacjentów, u których rozwija się zespół rakowiaka.²⁹ Wynika z przewlekłego zwłóknienia zastawek serca.³⁰

Dokładny mechanizm leżący u podstaw rozwoju CHD pozostaje niejasny. Istnieją jednak silne dowody na rolę 5-HT w fibrogenezie i stymulacji wzrostu fibroblastów w CHD.³¹³² Pomimo silnych dowodów na udział 5-HT w rozwoju CHD, znaczna część pacjentów z podwyższonym poziomem 5-HT w osoczu nie rozwija tej choroby, co sugeruje, że zaangażowane są inne mechanizmy biochemiczne lub genetyczne.³³³⁴

Sercowa patologia wywołana serotoninę prawdopodobnie zachodzi przez receptory 5-HT2B.³⁵ Sygnalizacja przez 5-HT2B indukuje zwiększoną ekspresję TGF-β1, kluczowego mediatora aktywacji miofibroblastów i odpowiedzi fibrogennych, który był również wcześniej związany z CHD.³⁶³⁷

Wiele badań wykazało kluczową rolę 5-HT nawet w rozwoju i progresji zwłóknienia, ponieważ wydawała się ona stymulować wzrost fibroblastów i fibrogenezę, powodując powikłania związane z zespołem rakowiaka, takie jak CHD, zwłóknienie krezki i zwłóknienie zaotrzewnowe.³⁸ CHD jest zjawiskiem wieloczynnikowym, potencjalnie występującym przez receptory 5-HT2B, receptory sprzężone z białkiem G, które pośredniczą w sygnałach mitogennych fibroblastów i komórek mięśni gładkich.³⁹

W transgenicznych myszach nadekspresja 5-HT2BR, szczególnie w sercu, powodowała przerost serca i odkładanie macierzy pozakomórkowej.⁴⁰ Specyficzne antagonisty 5-HT2BR zmniejszały zwłóknienie i chroniły przed niewydolnością prawej komory w mysim modelu z nadciśnieniem płucnym.⁴¹

Główne konsekwencje docierania tych wazoaktywnych substancji neuroendokrynnych do serca to charakterystyczne złogi włóknistej tkanki podobne do płytki miażdżycowej, najczęściej wpływające na aparat zastawki trójdzielnej i zastawkę płucną. Powoduje to pogrubienie płatków zastawek z krótkimi, pogrubionymi i zespolonymi strunami ścięgnistymi i mięśniami brodawkowatymi, co prowadzi do mieszanej niedomykalności zastawki trójdzielnej (dominującej) i stenozy, oraz mieszanej niedomykalności zastawki płucnej (dominującej) i stenozy.⁴²

Co ciekawe, lewa strona serca jest stosunkowo chroniona przed CHD, ponieważ peptydy wazoaktywne są dezaktywowane po przejściu przez płuca, zanim dotrą do lewego przedsionka.⁴³ Jednak w przypadku wewnątrzsercowego przecieku prawo-lewego (np. przetrwałego otworu owalnego) lub pierwotnego rakowiaka oskrzeli, może również wystąpić choroba lewostronnych zastawek, chociaż występuje ona u mniej niż 10% wszystkich pacjentów.⁴⁴

Mechanizm zwłóknień w zespole rakowiaka

Guzy rakowiaka mogą być związane z koncentrycznym i elastycznym stwardnieniem naczyń, co prowadzi do obliteracji światła naczyń i niedokrwienia. Częstym znaleziskiem jest elastoza i włóknienie, które otaczają gniazda komórek nowotworowych i które powodują matowienie zajętych tkanek i węzłów chłonnych.⁴⁵

5-HT może stymulować syntezę macierzy pozakomórkowej (ECM), prowadząc do zwłóknienia i powodując niedrożność jelit i chorobę serca w przebiegu zespołu rakowiaka w perspektywie długoterminowej. Istnieje korelacja między tymi powikłaniami a podwyższonym poziomem 5-HIAA w moczu.⁴⁶

Inną substancją, która może być zaangażowana w patofizjologię zwłóknienia krezki, jest TGF-beta, który może odgrywać kluczową rolę w fibrogenezie ze względu na znaną zdolność do stymulowania syntezy kolagenu.⁴⁷

Kryzys rakowiaka

Kryzys rakowiaka to potencjalnie zagrażające życiu powikłanie charakteryzujące się ciężką niestabilnością hemodynamiczną, zaczerwienieniem skóry, skurczem oskrzeli i niedociśnieniem, często wywołanym przez operację, znieczulenie lub martwicę guza.⁴⁸

Kryzys rakowiaka wywołany przez Lutetium-177-Dotatate powstaje, gdy indukcja radioterapii powoduje nagłe, masowe uwolnienie ponad 40 hormonów z komórek nowotworowych, przede wszystkim serotoniny, histaminy i katecholamin. Liza guza jest przypuszczalną etiologią kryzysu rakowiaka po terapii radionuklidami. Częstość występowania kryzysu rakowiaka szacuje się na 1-2% odbiorców leczenia, chociaż dokładna częstość nie jest dobrze znana, częściowo z powodu słabej definicji kryteriów kwalifikujących rozpoznanie tego zdarzenia niepożądanego.⁴⁹

Guzy zlokalizowane w jelicie cienkim lub prawostronnej okrężnicy, większe obciążenie nowotworem, choroba przerzutowa do wątroby oraz wysokie poziomy kwasu 5-hydroksyindoloctowego w surowicy lub moczu i chromograniny A w surowicy wiązały się z wyższym ryzykiem rozwoju kryzysu rakowiaka.⁵⁰

Leczenie zespołu rakowiaka

Postępowanie w zespole rakowiaka koncentruje się na hamowaniu uwalniania amin biogennych i zmniejszeniu masy guza przy użyciu wielu modalności.⁵¹ Podstawowym filarem leczenia zespołu rakowiaka jest stosowanie analogów somatostatyny, takich jak oktreotyd i lanreotyd.⁵²⁵³

Analogi somatostatyny (SSA) są podstawą leczenia medycznego.⁵⁴ Terapia analogami somatostatyny (SSA) od kilku dekad jest podstawą terapii antysekrecyjnej w funkcjonujących nowotworach neuroendokrynnych.⁵⁵ Oprócz zarządzania objawowego, ostatnie badania wykazują, że SSA wywierają efekty antyproliferacyjne i hamują wzrost guza poprzez receptor somatostatyny 2 (SSTR2).⁵⁶

Telotristat etyl (TE) to nowy, doustny, obwodowy inhibitor tryptofanhydroksylazy. Ma on dużą masę cząsteczkową i cząsteczki kwasowe, co uniemożliwia przenikanie leku przez barierę krew-mózg, tworząc w ten sposób selektywność fizjologiczną dla TPH1; TE powoduje znaczne zmniejszenie stężenia 5-HT w jelicie bez wpływu na stężenie 5-HT w ośrodkowym układzie nerwowym.⁵⁷

PRRT (Peptide Receptor Radionuclide Therapy) to ukierunkowane leczenie systemowe zaawansowanych nowotworów neuroendokrynnych, które wyrażają receptory somatostatyny, wykorzystujące znakowane radioaktywnie analogi somatostatyny (np. lutet-177) do dostarczania zlokalizowanego promieniowania jonizującego do komórek nowotworowych.⁵⁸

Resekcja pierwotnych nowotworów neuroendokrynnych przewodu pokarmowego i oskrzeli u pacjentów z zespołem rakowiaka jest często lecząca. W przypadku pacjentów z przerzutami do wątroby, chirurgiczna redukcja guza, chociaż nie lecząca, może złagodzić objawy i, w niektórych przypadkach, przedłużyć przeżycie.⁵⁹

Kolejne rozdziały

Zapraszamy do dalszego czytania naszego leksykonu.

Wybierz kolejny rozdział z menu poniżej, aby otworzyć nową podstronę kompedium wiedzy i uzyskać szczegółowe informację o leku, substancji lub chorobie.

Materiały źródłowe

#1 Carcinoid Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK448096/
Carcinoid syndrome is a rare clinical condition caused by metastatic, well-differentiated neuroendocrine tumors, primarily originating in the midgut and associated with liver metastases. These tumors secrete biogenic amines, particularly serotonin, leading to hallmark symptoms such as flushing, diarrhea, bronchospasm, and systemic complications like carcinoid heart disease. […] Carcinoid syndrome arises from the release of biologically active amines and peptides into the systemic circulation, bypassing the liver’s first-pass metabolism. The liver normally inactivates these substances, but liver metastases from neuroendocrine tumors can allow these products to enter the circulation and exert systemic effects. […] Neuroendocrine tumors secrete about 40 types of biologically active amines and peptides, with serotonin being the most significant in carcinoid syndrome. While only 1% of dietary tryptophan is normally converted to serotonin, up to 70% may be diverted in these tumors.
#2 Carcinoid syndrome: update on the pathophysiology and treatment | Clinics
https://www.elsevier.es/en-revista-clinics-22-articulo-carcinoid-syndrome-update-on-pathophysiology-S1807593222011310
Approximately 30-40% of patients with well-differentiated neuroendocrine tumors present with carcinoid syndrome, which is a paraneoplastic syndrome associated with the secretion of several humoral factors. […] Carcinoid syndrome (CS) is a paraneoplastic syndrome associated with the secretion of several humoral factors, such as polypeptides, vasoactive amines, and prostaglandins. […] More than 40 substances have been identified as being potentially related to CS; however, their individual contributions in triggering different carcinoid symptoms and complications, such as CHD, remain unclear. These substances include serotonin (5-HT), which appears to be the primary marker associated with the syndrome, as well as histamine, kallikrein, prostaglandins, and tachykinins. […] The exact mechanism underlying the development of CHD remains unclear. However, there is strong evidence for the role of 5-HT in the fibrogenesis and stimulation of fibroblast growth in CHD.
#3 Carcinoid syndrome: update on the pathophysiology and treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC6096975/
Approximately 30-40% of patients with well-differentiated neuroendocrine tumors present with carcinoid syndrome, which is a paraneoplastic syndrome associated with the secretion of several humoral factors. […] More than 40 substances have been identified as being potentially related to carcinoid syndrome; however, their individual contributions in triggering different carcinoid symptoms and complications, such as carcinoid heart disease, remain unclear. These substances include serotonin (5-HT), which appears to be the primary marker associated with the syndrome, as well as histamine, kallikrein, prostaglandins, and tachykinins. […] The exact mechanism underlying the development of carcinoid heart disease remains unclear. However, there is strong evidence for the role of 5-HT in the fibrogenesis and stimulation of fibroblast growth in carcinoid heart disease.
#4 Carcinoid syndrome: update on the pathophysiology and treatment | Clinics
https://www.elsevier.es/es-revista-clinics-22-articulo-carcinoid-syndrome-update-on-pathophysiology-S1807593222011310
Approximately 30-40% of patients with well-differentiated neuroendocrine tumors present with carcinoid syndrome, which is a paraneoplastic syndrome associated with the secretion of several humoral factors. […] More than 40 substances have been identified as being potentially related to CS; however, their individual contributions in triggering different carcinoid symptoms and complications, such as CHD, remain unclear. These substances include serotonin (5-HT), which appears to be the primary marker associated with the syndrome, as well as histamine, kallikrein, prostaglandins, and tachykinins. […] Given the complexity involving the origin, diagnosis and management of patients with CS, we have undertaken a comprehensive review to update our knowledge about the pathophysiology, diagnostic tools and treatment options for this syndrome.
#5 Carcinoid Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK448096/
Carcinoid syndrome is a rare clinical condition caused by metastatic, well-differentiated neuroendocrine tumors, primarily originating in the midgut and associated with liver metastases. These tumors secrete biogenic amines, particularly serotonin, leading to hallmark symptoms such as flushing, diarrhea, bronchospasm, and systemic complications like carcinoid heart disease. […] Carcinoid syndrome arises from the release of biologically active amines and peptides into the systemic circulation, bypassing the liver’s first-pass metabolism. The liver normally inactivates these substances, but liver metastases from neuroendocrine tumors can allow these products to enter the circulation and exert systemic effects. […] Neuroendocrine tumors secrete about 40 types of biologically active amines and peptides, with serotonin being the most significant in carcinoid syndrome. While only 1% of dietary tryptophan is normally converted to serotonin, up to 70% may be diverted in these tumors.
#6 Malignant Carcinoid Syndrome: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/282515-overview
Malignant carcinoid syndrome is characterized by an array of signs and symptoms in particular, hot, red flushing of the face; severe and debilitating diarrhea; and asthma attacks caused by vasoactive hormones secreted by metastases from carcinoid tumors. […] Carcinoids do not produce the malignant carcinoid syndrome until they are no longer confined to the small bowel or mesentery, perhaps because the liver breaks down the secretory products of tumors restricted to those locations. […] Pathophysiology is closely related to the sites of the primary tumors. When these tumors spread to the liver, patients usually begin to develop malignant carcinoid syndrome. In fact, this syndrome develops when vasoactive substances produced by a carcinoid tumor escape hepatic degradation and gain access to the systemic circulation.
#7 Malignant Carcinoid Syndrome: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/282515-overview
Malignant carcinoid syndrome is characterized by an array of signs and symptoms in particular, hot, red flushing of the face; severe and debilitating diarrhea; and asthma attacks caused by vasoactive hormones secreted by metastases from carcinoid tumors. […] Carcinoids do not produce the malignant carcinoid syndrome until they are no longer confined to the small bowel or mesentery, perhaps because the liver breaks down the secretory products of tumors restricted to those locations. […] Pathophysiology is closely related to the sites of the primary tumors. When these tumors spread to the liver, patients usually begin to develop malignant carcinoid syndrome. In fact, this syndrome develops when vasoactive substances produced by a carcinoid tumor escape hepatic degradation and gain access to the systemic circulation.
#8 Gastrointestinal Neuroendocrine Tumors and Carcinoid Syndrome – Endocrine and Metabolic Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/gastrointestinal-and-pancreatic-neuroendocrine-tumors-nets/gastrointestinal-neuroendocrine-tumors-and-carcinoid-syndrome
Carcinoid syndrome is a complex of symptoms and signs that develops in some people with endocrinologically active neuroendocrine tumors and is characterized by cutaneous flushing, abdominal cramps, and diarrhea. […] The syndrome results from vasoactive substances (including serotonin, bradykinin, histamine, prostaglandins, polypeptide hormones) secreted by the tumor, which is typically a metastatic intestinal neuroendocrine tumor. […] Carcinoid syndrome is usually due to endocrinologically active NETs that develop from neuroendocrine cells (mostly in the ileum) and produce serotonin. […] An intestinal serotonin-producing NET does not usually cause carcinoid syndrome unless hepatic metastases have occurred because metabolic products released by the tumor are rapidly destroyed by blood and liver enzymes in the portal circulation.
#9 Carcinoid syndrome | Radiology Reference Article | Radiopaedia.org
https://radiopaedia.org/articles/carcinoid-syndrome?embed_domain=staging.radpair.com&lang=us
Carcinoid syndrome refers to a spectrum of symptoms that result from excessive hormone (mainly serotonin) secretion. […] Carcinoid syndrome can occur as a paraneoplastic syndrome in the context of a neuroendocrine tumor. The presence of the carcinoid syndrome often indicates hepatic metastatic disease, however, extraintestinal neuroendocrine tumor can also cause carcinoid syndrome without hepatic metastasis as serotonin secretion can bypass the enterohepatic circulation.
#10 Gastrointestinal Neuroendocrine Tumors and Carcinoid Syndrome – Endocrine and Metabolic Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/gastrointestinal-and-pancreatic-neuroendocrine-tumors-nets/gastrointestinal-neuroendocrine-tumors-and-carcinoid-syndrome
Hepatic metastases, however, release metabolic products via the hepatic veins directly into the systemic circulation. […] Serotonin, the primary hormone produced by some NETs, acts on smooth muscle to cause diarrhea, colic, and malabsorption. […] Histamine and bradykinin, which are produced in smaller amounts, cause flushing through their vasodilator effects. […] Some patients develop right-sided endocardial fibrosis, leading to pulmonic stenosis and tricuspid regurgitation. […] The role of prostaglandins and various polypeptide hormones, which may be produced by paracrine cells, awaits further investigation. […] Guidelines recommend the use of either octreotide or lanreotide as first-line treatment for patients with symptomatic carcinoid syndrome. […] Certain symptoms, including flushing, have been relieved by SSAs (which inhibit release of most hormones) without lowering urinary 5-HIAA or gastrin.
#11 Carcinoid Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK448096/
Carcinoid syndrome is a rare clinical condition caused by metastatic, well-differentiated neuroendocrine tumors, primarily originating in the midgut and associated with liver metastases. These tumors secrete biogenic amines, particularly serotonin, leading to hallmark symptoms such as flushing, diarrhea, bronchospasm, and systemic complications like carcinoid heart disease. […] Carcinoid syndrome arises from the release of biologically active amines and peptides into the systemic circulation, bypassing the liver’s first-pass metabolism. The liver normally inactivates these substances, but liver metastases from neuroendocrine tumors can allow these products to enter the circulation and exert systemic effects. […] Neuroendocrine tumors secrete about 40 types of biologically active amines and peptides, with serotonin being the most significant in carcinoid syndrome. While only 1% of dietary tryptophan is normally converted to serotonin, up to 70% may be diverted in these tumors.
#12 Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies
https://www.mdpi.com/1422-0067/24/4/3610
This paper provides a state-of-the-art overview of in vitro and in vivo models in NETs with carcinoid syndrome, highlighting the future developments and therapeutic approaches in this field. […] Several substances have been identified as being potentially related to CS manifestations and include mostly amines (serotonin, 5-hydroxytryptophan, norepinephrine, dopamine, histamine), but also many different polypeptides (kallikrein, pancreatic polypeptide, bradykinin, motilin, somatostatin, insulin, S-100 protein, vasoactive intestinal peptide, neuropeptide K, substance P, neurokinins, ACTH, gastrin, growth hormone, peptide YY, glucagon, endorphins, neurotensin, chromogranin A) and prostaglandins. […] The relative impact of any of them for triggering particular symptoms and complications of CS remains unclear, but serotonin (5-HT) and metabolites from the 5-HT pathway seem to play a crucial role.
#13 Carcinoid syndrome: update on the pathophysiology and treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC6096975/
Approximately 30-40% of patients with well-differentiated neuroendocrine tumors present with carcinoid syndrome, which is a paraneoplastic syndrome associated with the secretion of several humoral factors. […] More than 40 substances have been identified as being potentially related to carcinoid syndrome; however, their individual contributions in triggering different carcinoid symptoms and complications, such as carcinoid heart disease, remain unclear. These substances include serotonin (5-HT), which appears to be the primary marker associated with the syndrome, as well as histamine, kallikrein, prostaglandins, and tachykinins. […] The exact mechanism underlying the development of carcinoid heart disease remains unclear. However, there is strong evidence for the role of 5-HT in the fibrogenesis and stimulation of fibroblast growth in carcinoid heart disease.
#14 Carcinoid syndrome: update on the pathophysiology and treatment | Clinics
https://www.elsevier.es/en-revista-clinics-22-articulo-carcinoid-syndrome-update-on-pathophysiology-S1807593222011310
Approximately 30-40% of patients with well-differentiated neuroendocrine tumors present with carcinoid syndrome, which is a paraneoplastic syndrome associated with the secretion of several humoral factors. […] Carcinoid syndrome (CS) is a paraneoplastic syndrome associated with the secretion of several humoral factors, such as polypeptides, vasoactive amines, and prostaglandins. […] More than 40 substances have been identified as being potentially related to CS; however, their individual contributions in triggering different carcinoid symptoms and complications, such as CHD, remain unclear. These substances include serotonin (5-HT), which appears to be the primary marker associated with the syndrome, as well as histamine, kallikrein, prostaglandins, and tachykinins. […] The exact mechanism underlying the development of CHD remains unclear. However, there is strong evidence for the role of 5-HT in the fibrogenesis and stimulation of fibroblast growth in CHD.
#15 A Critical Appraisal Proposed Mediators of Carcinoid Syndrome | Endocrine Society
https://www.endocrine.org/journals/endocrine-reviews/a-critical-appraisal-proposed-mediators-of-carcinoid-syndrome
Carcinoid syndrome (CS) is a debilitating disease that affects approximately 20% of patients with neuroendocrine neoplasms (NEN). […] At present, symptom control is hampered by an incomplete understanding of the pathophysiology of this syndrome. […] Overall, evidence for the putative mediators of CS was scarce and often of poor quality. Based on the available literature, data are only sufficient to agree on the role of serotonin as a mediator of CS-associated diarrhea and fibrosis. A direct role for tachykinins and an indirect role of catecholamines in the pathogenesis of CS is suggested by several studies. Currently, there is insufficient evidence to link histamine, bradykinin, kallikrein, prostaglandins, or motilin to CS. […] To summarize, available literature only sufficiently appoints serotonin and suggests a role for tachykinins and catecholamines as mediators of CS, with insufficient evidence for other putative mediators. Descriptions of CS should be revised to focus on these proven hormonal associations to be more accurate, and further research is needed into other potential mediators.
#16 A Critical Appraisal Proposed Mediators of Carcinoid Syndrome | Endocrine Society
https://www.endocrine.org/journals/endocrine-reviews/a-critical-appraisal-proposed-mediators-of-carcinoid-syndrome
Carcinoid syndrome (CS) is a debilitating disease that affects approximately 20% of patients with neuroendocrine neoplasms (NEN). […] At present, symptom control is hampered by an incomplete understanding of the pathophysiology of this syndrome. […] Overall, evidence for the putative mediators of CS was scarce and often of poor quality. Based on the available literature, data are only sufficient to agree on the role of serotonin as a mediator of CS-associated diarrhea and fibrosis. A direct role for tachykinins and an indirect role of catecholamines in the pathogenesis of CS is suggested by several studies. Currently, there is insufficient evidence to link histamine, bradykinin, kallikrein, prostaglandins, or motilin to CS. […] To summarize, available literature only sufficiently appoints serotonin and suggests a role for tachykinins and catecholamines as mediators of CS, with insufficient evidence for other putative mediators. Descriptions of CS should be revised to focus on these proven hormonal associations to be more accurate, and further research is needed into other potential mediators.
#17 Carcinoid Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK448096/
Carcinoid syndrome is a rare clinical condition caused by metastatic, well-differentiated neuroendocrine tumors, primarily originating in the midgut and associated with liver metastases. These tumors secrete biogenic amines, particularly serotonin, leading to hallmark symptoms such as flushing, diarrhea, bronchospasm, and systemic complications like carcinoid heart disease. […] Carcinoid syndrome arises from the release of biologically active amines and peptides into the systemic circulation, bypassing the liver’s first-pass metabolism. The liver normally inactivates these substances, but liver metastases from neuroendocrine tumors can allow these products to enter the circulation and exert systemic effects. […] Neuroendocrine tumors secrete about 40 types of biologically active amines and peptides, with serotonin being the most significant in carcinoid syndrome. While only 1% of dietary tryptophan is normally converted to serotonin, up to 70% may be diverted in these tumors.
#18 Carcinoid syndrome – Wikipedia
https://en.wikipedia.org/wiki/Carcinoid_syndrome
Tryptophan metabolism is altered in the carcinoid syndrome. With neuroendocrine tumors, there is a shift in conversion of tryptophan to serotonin from the normal 1% to as high as 70%. Increased amounts of serotonin lead to increased gut motility causing the diarrhea seen in carcinoid syndrome. Increased amounts of serotonin can also cause the flushing seen as the main symptom of carcinoid syndrome. Tryptophan is also needed for niacin synthesis which can be a cause for pellagra associated with carcinoid syndrome. In the pulmonary neuroendocrine tumors or metastases, histamine release and kallikrein metabolism are the vasoactive mediators of flushing and the other symptoms of carcinoid syndrome.
#19 The role of serotonin inhibition within the treatment of carcinoid syndrome in: Endocrine Oncology Volume 3 Issue 1 (2023)
https://eo.bioscientifica.com/view/journals/eo/3/1/EO-22-0077.xml
Normally only 1% of dietary tryptophan is metabolised to 5-HT; however, in CS, the proportion is 70%. Blood 5-HT concentration is increased via 5-HT-secreting hepatic lesions which bypasses the liver to reach the systemic circulation. […] A high 5-HT is thought to be the main mediator of diarrhoea by acting directly on cell membrane receptors of enteric neurons. This increases peristalsis and impedes intestinal absorption. 5-HT may stimulate the synthesis of extracellular matrix (ECM), leading to fibrosis and resulting in bowel obstruction and carcinoid heart disease in the long term. There is a correlation between these complications and raised urine 5-HIAA. […] Management of CS can be achieved through a combination of medical, surgical and loco-regional interventional radiological procedures. Some of these therapies will have dual syndrome control and anti-tumour benefit.
#20 Carcinoid Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK448096/
Excess serotonin causes increased gastrointestinal motility and hypersecretion, leading to diarrhea, one of the hallmarks of carcinoid syndrome. […] Carcinoid syndrome presents a range of symptoms due to the vasodilatory effects of biologically active amines, peptides, and prostaglandins. […] The management of carcinoid syndrome centers on suppressing biogenic amine release and reducing tumor burden using multiple modalities. […] Somatostatin analogs (SSA) are the cornerstone of medical management. […] PRRT is a targeted systemic treatment for advanced neuroendocrine tumors that express somatostatin receptors, utilizing radiolabeled somatostatin analogs (eg, lutetium-177) to deliver localized ionizing radiation to tumor cells. […] Carcinoid crisis is a potentially life-threatening complication characterized by severe hemodynamic instability, flushing, bronchoconstriction, and hypotension, often triggered by surgery, anesthesia, or tumor necrosis.
#21 Carcinoid syndrome – Wikipedia
https://en.wikipedia.org/wiki/Carcinoid_syndrome
Tryptophan metabolism is altered in the carcinoid syndrome. With neuroendocrine tumors, there is a shift in conversion of tryptophan to serotonin from the normal 1% to as high as 70%. Increased amounts of serotonin lead to increased gut motility causing the diarrhea seen in carcinoid syndrome. Increased amounts of serotonin can also cause the flushing seen as the main symptom of carcinoid syndrome. Tryptophan is also needed for niacin synthesis which can be a cause for pellagra associated with carcinoid syndrome. In the pulmonary neuroendocrine tumors or metastases, histamine release and kallikrein metabolism are the vasoactive mediators of flushing and the other symptoms of carcinoid syndrome.
#22 Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies
https://www.mdpi.com/1422-0067/24/4/3610
The 5-HT biosynthesis is catalyzed by TPH of which there are two isoforms: TPH-1, expressed in enterochromaffin cells of the gastrointestinal tract, and TPH-2, that is considered to be the source of the central neurotransmitter pool of 5-HT and predominantly expressed in raphe neurons of the brainstem and myenteric neurons in the gut. […] The majority of blood 5-HT is synthesized by TPH-1 that emerged as a possible therapeutic target for the development of specific inhibitors. […] Many studies have demonstrated the pivotal role of 5-HT even in development and progression of fibrosis, because it appeared able to stimulate fibroblast growth and fibrogenesis, resulting in CS-associated complications such as CHD, mesenteric and retroperitoneal fibrosis. […] CHD is a multifactorial phenomenon possibly occurring through 5-HT2BR, a G-protein coupled receptor that mediates fibroblasts and smooth muscle cells mitogenic signals, and that induces an increased expression of TGF-Î²1. […] In transgenic mice, the overexpression of 5-HT2BR, specifically in the heart, resulted in cardiac hypertrophy and extracellular matrix deposition. […] Specific antagonists of 5-HT2BR reduced fibrosis and protected against right ventricle failure in a mice model with pulmonary hypertension.
#23 Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies
https://www.mdpi.com/1422-0067/24/4/3610
The 5-HT biosynthesis is catalyzed by TPH of which there are two isoforms: TPH-1, expressed in enterochromaffin cells of the gastrointestinal tract, and TPH-2, that is considered to be the source of the central neurotransmitter pool of 5-HT and predominantly expressed in raphe neurons of the brainstem and myenteric neurons in the gut. […] The majority of blood 5-HT is synthesized by TPH-1 that emerged as a possible therapeutic target for the development of specific inhibitors. […] Many studies have demonstrated the pivotal role of 5-HT even in development and progression of fibrosis, because it appeared able to stimulate fibroblast growth and fibrogenesis, resulting in CS-associated complications such as CHD, mesenteric and retroperitoneal fibrosis. […] CHD is a multifactorial phenomenon possibly occurring through 5-HT2BR, a G-protein coupled receptor that mediates fibroblasts and smooth muscle cells mitogenic signals, and that induces an increased expression of TGF-Î²1. […] In transgenic mice, the overexpression of 5-HT2BR, specifically in the heart, resulted in cardiac hypertrophy and extracellular matrix deposition. […] Specific antagonists of 5-HT2BR reduced fibrosis and protected against right ventricle failure in a mice model with pulmonary hypertension.
#24 Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies
https://www.mdpi.com/1422-0067/24/4/3610
Actually, there are two main approaches in the management of CS: the direct inhibition of hormonal secretion and the control of tumor burden, thereby reducing the disease volume and indirectly the hormonal production. […] The first approach is represented by the use of somatostatin analogues (octreotide, lanreotide and pasireotide), which provide rapid symptom relief. […] Telotristat ethyl, a tryptophan hydroxylase (TPH) inhibitor, the rate-limiting enzyme in 5-HT biosynthesis, represents a novel treatment in patients with CS. […] Although there are several drugs available for the treatment of CS, the lack of therapeutic response, poor tolerance or resistance to drugs are often reported. […] Preclinical models are indispensable tools for investigating the pathogenesis, mechanisms for tumor progression and new therapeutic approaches for cancer.
#25 Malignant Carcinoid Syndrome: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/282515-overview
Physiologically, serotonin causes vasodilation and can increase blood clotting by stimulating platelet aggregation, which may result in disseminated intravascular coagulation (DIC); however, serotonin is converted to 5-HIAA in the body. […] The molecules listed above are responsible for the extreme symptoms of this condition. For example, the reason some patients develop heart disease is not definitively known, but the serotonin produced by the tumor is probably involved. Bronchial constriction, which accounts for the asthmalike attacks, seems related to the tumoral tachykinins. Carcinoid diarrhea has been correlated with circulating tachykinins. […] Serotonin is derived from the amino acid tryptophan, which also serves as a precursor to niacin and several proteins. Increased metabolism of tryptophan by the tumor has been linked to symptoms in patients with carcinoid.
#26 Carcinoid syndrome: update on the pathophysiology and treatment | Clinics
https://www.elsevier.es/en-revista-clinics-22-articulo-carcinoid-syndrome-update-on-pathophysiology-S1807593222011310
5-HT secreted by NETs appears to play a central role in MF. A recent study demonstrated a significant association of MF with elevated urinary 5-HIAA levels, suggesting a potential causal relationship. […] The diagnosis of CS requires the combination of carcinoid symptoms and evidence of elevated levels of 5-HIAA in a 24-h urine sample. […] The main pillar of treatment for CS is the use of somatostatin analogues, such as octreotide and lanreotide.
#27 SciELO Brazil – Carcinoid syndrome: update on the pathophysiology and treatment Carcinoid syndrome: update on the pathophysiology and treatment
https://www.scielo.br/j/clin/a/TJBtjyHRK9DFDhWKP4dhK4J/
Despite the strong evidence of 5-HT involvement in the development of carcinoid heart disease, a significant proportion of patients with elevated plasma levels of 5-HT do not develop this condition, which suggests that there are other biochemical or genetic mechanisms involved. […] 5-HT secreted by neuroendocrine tumors appears to play a central role in mesenteric fibrosis. A recent study demonstrated a significant association of mesenteric fibrosis with elevated urinary 5-HIAA levels, suggesting a potential causal relationship. […] The diagnosis of carcinoid syndrome requires the combination of carcinoid symptoms and evidence of elevated levels of 5-HIAA in a 24-h urine sample. […] The main pillar of treatment for carcinoid syndrome is the use of somatostatin analogues, such as octreotide and lanreotide. […] However, studies suggest that their use does not lead to regression of carcinoid syndrome or prevent its occurrence.
#28 Carcinoid syndrome: update on the pathophysiology and treatment | Clinics
https://www.elsevier.es/es-revista-clinics-22-articulo-carcinoid-syndrome-update-on-pathophysiology-S1807593222011310
The exact mechanism underlying the development of CHD remains unclear. However, there is strong evidence for the role of 5-HT in the fibrogenesis and stimulation of fibroblast growth in CHD. […] Despite the strong evidence of 5-HT involvement in the development of CHD, a significant proportion of patients with elevated plasma levels of 5-HT do not develop this condition, which suggests that there are other biochemical or genetic mechanisms involved. […] A recent study demonstrated a significant association of MF with elevated urinary 5-HIAA levels, suggesting a potential causal relationship. Another study with 52 patients with midgut NETs demonstrated that elevated platelet 5-HT is associated with the presence of a mesenteric mass.
#29 Carcinoid heart disease | Radiology Reference Article | Radiopaedia.org
https://radiopaedia.org/articles/carcinoid-heart-disease-1?lang=us
Carcinoid heart disease, also known as Hedinger syndrome, is a known complication of neuroendocrine tumors (NETs) and is particularly prevalent in patients who develop carcinoid syndrome. […] Ordinarily, vasoactive neuroendocrine substances (serotonin, bradykinin, histamine, prostaglandin, etc.) produced from NETs that enter the bloodstream are inactivated by the liver. However, in the presence of liver metastases from these tumors, the vasoactive neuroendocrine substances can bypass the liver and affect the right side of the heart. […] Although the exact mechanism is unclear, the main consequences of these vasoactive neuroendocrine substances reaching the heart are characteristic plaque-like deposits of fibrous tissue, most commonly affecting the tricuspid valve apparatus and the pulmonary valve. This causes thickening of the valve leaflets with short, thickened, and fused chordae and papillary muscles, which results in mixed tricuspid regurgitation (predominant) and stenosis, and mixed pulmonary regurgitation (predominant) and stenosis. […] Furthermore, in the presence of an intracardiac right-to-left shunt (e.g. patent foramen ovale) or a primary bronchial carcinoid tumor, left-sided disease can also occur, although this occurs in fewer than 10% of all affected patients.
#30 Complications from carcinoid syndrome: review of the current evidence – ecancer
https://ecancer.org/en/journal/article/662-complications-from-carcinoid-syndrome-review-of-the-current-evidence
Patients with well-differentiated neuroendocrine tumours may develop carcinoid syndrome (CS), which is characterised by flushing, abdominal cramps, diarrhoea, and bronchospasms. […] Despite it not being well described yet, current evidence suggests the pathogenesis of such fibrogenic complications relies on signalling through 5-HT2B and TGF-1. […] Although the precise pathogenesis remains elusive, these substances are implicated in the development of CS. […] CHD results from chronic fibrotic degeneration of the cardiac valve leaflets. […] It was proposed that the vasoactive substances produced and secreted by the tumours induce myofibroblast proliferation and local deposition of extracellular matrix, ultimately leading to the emergence of endocardial plaques composed of matrix-rich fibrous tissues.
#31 Carcinoid syndrome: update on the pathophysiology and treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC6096975/
Approximately 30-40% of patients with well-differentiated neuroendocrine tumors present with carcinoid syndrome, which is a paraneoplastic syndrome associated with the secretion of several humoral factors. […] More than 40 substances have been identified as being potentially related to carcinoid syndrome; however, their individual contributions in triggering different carcinoid symptoms and complications, such as carcinoid heart disease, remain unclear. These substances include serotonin (5-HT), which appears to be the primary marker associated with the syndrome, as well as histamine, kallikrein, prostaglandins, and tachykinins. […] The exact mechanism underlying the development of carcinoid heart disease remains unclear. However, there is strong evidence for the role of 5-HT in the fibrogenesis and stimulation of fibroblast growth in carcinoid heart disease.
#32 SciELO Brazil – Carcinoid syndrome: update on the pathophysiology and treatment Carcinoid syndrome: update on the pathophysiology and treatment
https://www.scielo.br/j/clin/a/TJBtjyHRK9DFDhWKP4dhK4J/
Approximately 30-40% of patients with well-differentiated neuroendocrine tumors present with carcinoid syndrome, which is a paraneoplastic syndrome associated with the secretion of several humoral factors. […] More than 40 substances have been identified as being potentially related to carcinoid syndrome; however, their individual contributions in triggering different carcinoid symptoms or complications, such as carcinoid heart disease, remain unclear. These substances include serotonin (5-HT), which appears to be the primary marker associated with the syndrome, as well as histamine, kallikrein, prostaglandins, and tachykinins. […] The exact mechanism underlying the development of carcinoid heart disease remains unclear. However, there is strong evidence for the role of 5-HT in the fibrogenesis and stimulation of fibroblast growth in carcinoid heart disease.
#33 Carcinoid syndrome: update on the pathophysiology and treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC6096975/
Despite the strong evidence of 5-HT involvement in the development of carcinoid heart disease, a significant proportion of patients with elevated plasma levels of 5-HT do not develop this condition, which suggests that there are other biochemical or genetic mechanisms involved. […] Another substance that may be involved in the pathophysiology of mesenteric fibrosis is TGF-beta, which may play a critical role in fibrogenesis due to its known ability to stimulate collagen synthesis.
#34 SciELO Brazil – Carcinoid syndrome: update on the pathophysiology and treatment Carcinoid syndrome: update on the pathophysiology and treatment
https://www.scielo.br/j/clin/a/TJBtjyHRK9DFDhWKP4dhK4J/
Despite the strong evidence of 5-HT involvement in the development of carcinoid heart disease, a significant proportion of patients with elevated plasma levels of 5-HT do not develop this condition, which suggests that there are other biochemical or genetic mechanisms involved. […] 5-HT secreted by neuroendocrine tumors appears to play a central role in mesenteric fibrosis. A recent study demonstrated a significant association of mesenteric fibrosis with elevated urinary 5-HIAA levels, suggesting a potential causal relationship. […] The diagnosis of carcinoid syndrome requires the combination of carcinoid symptoms and evidence of elevated levels of 5-HIAA in a 24-h urine sample. […] The main pillar of treatment for carcinoid syndrome is the use of somatostatin analogues, such as octreotide and lanreotide. […] However, studies suggest that their use does not lead to regression of carcinoid syndrome or prevent its occurrence.
#35 Complications from carcinoid syndrome: review of the current evidence – ecancer
https://ecancer.org/en/journal/article/662-complications-from-carcinoid-syndrome-review-of-the-current-evidence
An emerging body of evidence has pointed towards serotonin as the possible main causative agent of CHD. […] Serotonin-induced cardiopathy possibly occurs through 5-HT2B. […] Signalling through 5-HT2B induces an increased expression of TGF-1, a key mediator of myofibroblast activation and fibrogenic responses which has also been previously related to CHD. […] Despite serotonin being important, CHD is believed to be a multifactorial phenomenon, since several other mediators have been associated with CHD. […] Regardless of the still unknown precise underlying mechanism, fibrotic plaque deposition usually affects the downstream side of the valve leaflets and subvalvular apparatus. […] The accumulation of fibrosis leads to a progressive movement restriction, retraction and fixation, which are clinically transduced to right-sided valve stenosis, regurgitation, or a variable combination of both.
#36 Complications from carcinoid syndrome: review of the current evidence – ecancer
https://ecancer.org/en/journal/article/662-complications-from-carcinoid-syndrome-review-of-the-current-evidence
An emerging body of evidence has pointed towards serotonin as the possible main causative agent of CHD. […] Serotonin-induced cardiopathy possibly occurs through 5-HT2B. […] Signalling through 5-HT2B induces an increased expression of TGF-1, a key mediator of myofibroblast activation and fibrogenic responses which has also been previously related to CHD. […] Despite serotonin being important, CHD is believed to be a multifactorial phenomenon, since several other mediators have been associated with CHD. […] Regardless of the still unknown precise underlying mechanism, fibrotic plaque deposition usually affects the downstream side of the valve leaflets and subvalvular apparatus. […] The accumulation of fibrosis leads to a progressive movement restriction, retraction and fixation, which are clinically transduced to right-sided valve stenosis, regurgitation, or a variable combination of both.
#37 The role of serotonin inhibition within the treatment of carcinoid syndrome in: Endocrine Oncology Volume 3 Issue 1 (2023)
https://eo.bioscientifica.com/view/journals/eo/3/1/EO-22-0077.xml
Carcinoid syndrome is the most frequent hormonal complication associated with neuroendocrine neoplasms. It is caused by the secretion of several vasoactive substances, the most prominent being serotonin, which play a pathophysiological role in the clinical symptoms which characterise carcinoid syndrome. Therefore, the focus of carcinoid syndrome treatment is to reduce serotonin production and hence improve the patients quality of life. […] The tumour microenvironment has been recognised as a critical determinant of tumour progression. Svedja et al. investigated the crosstalk between tumour cells and fibroblasts. It was found the addition of a specific 5-HT2B receptor antagonist in the tumour cell-containing compartment inhibited the proliferation of KRJ-I cells and significantly reduced 5-HT release, while also reducing the synthesis of transforming growth factor beta-1 (TGF-1), connective tissue growth factor and fibroblast growth factor 2 (FGF2).
#38 Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies
https://www.mdpi.com/1422-0067/24/4/3610
The 5-HT biosynthesis is catalyzed by TPH of which there are two isoforms: TPH-1, expressed in enterochromaffin cells of the gastrointestinal tract, and TPH-2, that is considered to be the source of the central neurotransmitter pool of 5-HT and predominantly expressed in raphe neurons of the brainstem and myenteric neurons in the gut. […] The majority of blood 5-HT is synthesized by TPH-1 that emerged as a possible therapeutic target for the development of specific inhibitors. […] Many studies have demonstrated the pivotal role of 5-HT even in development and progression of fibrosis, because it appeared able to stimulate fibroblast growth and fibrogenesis, resulting in CS-associated complications such as CHD, mesenteric and retroperitoneal fibrosis. […] CHD is a multifactorial phenomenon possibly occurring through 5-HT2BR, a G-protein coupled receptor that mediates fibroblasts and smooth muscle cells mitogenic signals, and that induces an increased expression of TGF-Î²1. […] In transgenic mice, the overexpression of 5-HT2BR, specifically in the heart, resulted in cardiac hypertrophy and extracellular matrix deposition. […] Specific antagonists of 5-HT2BR reduced fibrosis and protected against right ventricle failure in a mice model with pulmonary hypertension.
#39 Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies
https://www.mdpi.com/1422-0067/24/4/3610
The 5-HT biosynthesis is catalyzed by TPH of which there are two isoforms: TPH-1, expressed in enterochromaffin cells of the gastrointestinal tract, and TPH-2, that is considered to be the source of the central neurotransmitter pool of 5-HT and predominantly expressed in raphe neurons of the brainstem and myenteric neurons in the gut. […] The majority of blood 5-HT is synthesized by TPH-1 that emerged as a possible therapeutic target for the development of specific inhibitors. […] Many studies have demonstrated the pivotal role of 5-HT even in development and progression of fibrosis, because it appeared able to stimulate fibroblast growth and fibrogenesis, resulting in CS-associated complications such as CHD, mesenteric and retroperitoneal fibrosis. […] CHD is a multifactorial phenomenon possibly occurring through 5-HT2BR, a G-protein coupled receptor that mediates fibroblasts and smooth muscle cells mitogenic signals, and that induces an increased expression of TGF-Î²1. […] In transgenic mice, the overexpression of 5-HT2BR, specifically in the heart, resulted in cardiac hypertrophy and extracellular matrix deposition. […] Specific antagonists of 5-HT2BR reduced fibrosis and protected against right ventricle failure in a mice model with pulmonary hypertension.
#40 Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies
https://www.mdpi.com/1422-0067/24/4/3610
The 5-HT biosynthesis is catalyzed by TPH of which there are two isoforms: TPH-1, expressed in enterochromaffin cells of the gastrointestinal tract, and TPH-2, that is considered to be the source of the central neurotransmitter pool of 5-HT and predominantly expressed in raphe neurons of the brainstem and myenteric neurons in the gut. […] The majority of blood 5-HT is synthesized by TPH-1 that emerged as a possible therapeutic target for the development of specific inhibitors. […] Many studies have demonstrated the pivotal role of 5-HT even in development and progression of fibrosis, because it appeared able to stimulate fibroblast growth and fibrogenesis, resulting in CS-associated complications such as CHD, mesenteric and retroperitoneal fibrosis. […] CHD is a multifactorial phenomenon possibly occurring through 5-HT2BR, a G-protein coupled receptor that mediates fibroblasts and smooth muscle cells mitogenic signals, and that induces an increased expression of TGF-Î²1. […] In transgenic mice, the overexpression of 5-HT2BR, specifically in the heart, resulted in cardiac hypertrophy and extracellular matrix deposition. […] Specific antagonists of 5-HT2BR reduced fibrosis and protected against right ventricle failure in a mice model with pulmonary hypertension.
#41 Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies
https://www.mdpi.com/1422-0067/24/4/3610
The 5-HT biosynthesis is catalyzed by TPH of which there are two isoforms: TPH-1, expressed in enterochromaffin cells of the gastrointestinal tract, and TPH-2, that is considered to be the source of the central neurotransmitter pool of 5-HT and predominantly expressed in raphe neurons of the brainstem and myenteric neurons in the gut. […] The majority of blood 5-HT is synthesized by TPH-1 that emerged as a possible therapeutic target for the development of specific inhibitors. […] Many studies have demonstrated the pivotal role of 5-HT even in development and progression of fibrosis, because it appeared able to stimulate fibroblast growth and fibrogenesis, resulting in CS-associated complications such as CHD, mesenteric and retroperitoneal fibrosis. […] CHD is a multifactorial phenomenon possibly occurring through 5-HT2BR, a G-protein coupled receptor that mediates fibroblasts and smooth muscle cells mitogenic signals, and that induces an increased expression of TGF-Î²1. […] In transgenic mice, the overexpression of 5-HT2BR, specifically in the heart, resulted in cardiac hypertrophy and extracellular matrix deposition. […] Specific antagonists of 5-HT2BR reduced fibrosis and protected against right ventricle failure in a mice model with pulmonary hypertension.
#42 Carcinoid heart disease | Radiology Reference Article | Radiopaedia.org
https://radiopaedia.org/articles/carcinoid-heart-disease-1?lang=us
Carcinoid heart disease, also known as Hedinger syndrome, is a known complication of neuroendocrine tumors (NETs) and is particularly prevalent in patients who develop carcinoid syndrome. […] Ordinarily, vasoactive neuroendocrine substances (serotonin, bradykinin, histamine, prostaglandin, etc.) produced from NETs that enter the bloodstream are inactivated by the liver. However, in the presence of liver metastases from these tumors, the vasoactive neuroendocrine substances can bypass the liver and affect the right side of the heart. […] Although the exact mechanism is unclear, the main consequences of these vasoactive neuroendocrine substances reaching the heart are characteristic plaque-like deposits of fibrous tissue, most commonly affecting the tricuspid valve apparatus and the pulmonary valve. This causes thickening of the valve leaflets with short, thickened, and fused chordae and papillary muscles, which results in mixed tricuspid regurgitation (predominant) and stenosis, and mixed pulmonary regurgitation (predominant) and stenosis. […] Furthermore, in the presence of an intracardiac right-to-left shunt (e.g. patent foramen ovale) or a primary bronchial carcinoid tumor, left-sided disease can also occur, although this occurs in fewer than 10% of all affected patients.
#43 Complications from carcinoid syndrome: review of the current evidence – ecancer
https://ecancer.org/en/journal/article/662-complications-from-carcinoid-syndrome-review-of-the-current-evidence
Interestingly, the left side of the heart is relatively protected from CHD because the vasoactive peptides are inactivated after passing through the lungs before they reach the left atrium. […] Although the literature is controversial on this topic, it is logical to think that maximum control of serotonin levels would prevent or at least delay the onset and progression of CHD. […] However, the medical treatment of established CHD relies on palliative measures such as loop diuretics, salt and fluid restriction to reduce oedema. […] The only definitive treatment for advanced CHD is valve replacement surgery or valvuloplasty. […] Despite the absence of prospective randomised studies, the literature recognises that cardiac surgery remarkably improves symptoms and reduces mortality in patients with severe CHD. […] The medical treatment of established fibrosis is still a clinical challenge as these complications are generally irreversible. […] Pathogenesis of these complications is likely secondary to serotonin overproduction and the associated activation of signalling pathways such as TGF-.
#44 Carcinoid heart disease | Radiology Reference Article | Radiopaedia.org
https://radiopaedia.org/articles/carcinoid-heart-disease-1?lang=us
Carcinoid heart disease, also known as Hedinger syndrome, is a known complication of neuroendocrine tumors (NETs) and is particularly prevalent in patients who develop carcinoid syndrome. […] Ordinarily, vasoactive neuroendocrine substances (serotonin, bradykinin, histamine, prostaglandin, etc.) produced from NETs that enter the bloodstream are inactivated by the liver. However, in the presence of liver metastases from these tumors, the vasoactive neuroendocrine substances can bypass the liver and affect the right side of the heart. […] Although the exact mechanism is unclear, the main consequences of these vasoactive neuroendocrine substances reaching the heart are characteristic plaque-like deposits of fibrous tissue, most commonly affecting the tricuspid valve apparatus and the pulmonary valve. This causes thickening of the valve leaflets with short, thickened, and fused chordae and papillary muscles, which results in mixed tricuspid regurgitation (predominant) and stenosis, and mixed pulmonary regurgitation (predominant) and stenosis. […] Furthermore, in the presence of an intracardiac right-to-left shunt (e.g. patent foramen ovale) or a primary bronchial carcinoid tumor, left-sided disease can also occur, although this occurs in fewer than 10% of all affected patients.
#45 Carcinoid Tumor: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/986050-overview
Carcinoid tumors are of neuroendocrine origin and derived from primitive stem cells in the gut wall, especially the appendix. […] Carcinoid tumors can be associated with concentric and elastic vascular sclerosis that results in obliteration of vascular lumina and ischemia. A common finding is elastosis and fibrosis that surround nests of the tumor cells and that result in matting of the involved tissues and lymph nodes. […] Carcinoid tumors have high potential for metastasis. These cells produce a significant amount of beta-catenin, which enables the tumor cell adhesion, thus promoting metastasis. Induction of Raf1 results in decreased adhesion of carcinoid cells and may be important in the metastatic process.
#46 The role of serotonin inhibition within the treatment of carcinoid syndrome in: Endocrine Oncology Volume 3 Issue 1 (2023)
https://eo.bioscientifica.com/view/journals/eo/3/1/EO-22-0077.xml
Normally only 1% of dietary tryptophan is metabolised to 5-HT; however, in CS, the proportion is 70%. Blood 5-HT concentration is increased via 5-HT-secreting hepatic lesions which bypasses the liver to reach the systemic circulation. […] A high 5-HT is thought to be the main mediator of diarrhoea by acting directly on cell membrane receptors of enteric neurons. This increases peristalsis and impedes intestinal absorption. 5-HT may stimulate the synthesis of extracellular matrix (ECM), leading to fibrosis and resulting in bowel obstruction and carcinoid heart disease in the long term. There is a correlation between these complications and raised urine 5-HIAA. […] Management of CS can be achieved through a combination of medical, surgical and loco-regional interventional radiological procedures. Some of these therapies will have dual syndrome control and anti-tumour benefit.
#47 Carcinoid syndrome: update on the pathophysiology and treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC6096975/
Despite the strong evidence of 5-HT involvement in the development of carcinoid heart disease, a significant proportion of patients with elevated plasma levels of 5-HT do not develop this condition, which suggests that there are other biochemical or genetic mechanisms involved. […] Another substance that may be involved in the pathophysiology of mesenteric fibrosis is TGF-beta, which may play a critical role in fibrogenesis due to its known ability to stimulate collagen synthesis.
#48 Carcinoid Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK448096/
Excess serotonin causes increased gastrointestinal motility and hypersecretion, leading to diarrhea, one of the hallmarks of carcinoid syndrome. […] Carcinoid syndrome presents a range of symptoms due to the vasodilatory effects of biologically active amines, peptides, and prostaglandins. […] The management of carcinoid syndrome centers on suppressing biogenic amine release and reducing tumor burden using multiple modalities. […] Somatostatin analogs (SSA) are the cornerstone of medical management. […] PRRT is a targeted systemic treatment for advanced neuroendocrine tumors that express somatostatin receptors, utilizing radiolabeled somatostatin analogs (eg, lutetium-177) to deliver localized ionizing radiation to tumor cells. […] Carcinoid crisis is a potentially life-threatening complication characterized by severe hemodynamic instability, flushing, bronchoconstriction, and hypotension, often triggered by surgery, anesthesia, or tumor necrosis.
#49 Carcinoid crisis in Lutetium-177-Dotatate therapy of neuroendocrine tumors: an overview of pathophysiology, risk factors, recognition, and treatment | EJNMMI Reports | Full Text
https://ejhi.springeropen.com/articles/10.1186/s41824-024-00216-6
Lutetium-177-Dotatate induced carcinoid crisis arises when radiotherapy induction results in a sudden massive release of over 40 hormones from tumor cells, most notably serotonin, histamine, and catecholamines. Tumor lysis is the presumed etiology of carcinoid crisis after radionuclide therapy. The incidence of carcinoid crisis is estimated to range between 1 and 2% of treatment recipients, although the exact incidence is not well known, in part due to poor definition of criteria qualifying the diagnosis of this adverse event. […] Those suffering tumors located within the small intestine or right-sided colon, higher tumor burden, metastatic disease to the liver, and high levels of serum or urine 5-hydroxyindolacetic acid and serum chromogranin A were found to be at higher risk of developing carcinoid crisis.
#50 Carcinoid crisis in Lutetium-177-Dotatate therapy of neuroendocrine tumors: an overview of pathophysiology, risk factors, recognition, and treatment | EJNMMI Reports | Full Text
https://ejhi.springeropen.com/articles/10.1186/s41824-024-00216-6
Lutetium-177-Dotatate induced carcinoid crisis arises when radiotherapy induction results in a sudden massive release of over 40 hormones from tumor cells, most notably serotonin, histamine, and catecholamines. Tumor lysis is the presumed etiology of carcinoid crisis after radionuclide therapy. The incidence of carcinoid crisis is estimated to range between 1 and 2% of treatment recipients, although the exact incidence is not well known, in part due to poor definition of criteria qualifying the diagnosis of this adverse event. […] Those suffering tumors located within the small intestine or right-sided colon, higher tumor burden, metastatic disease to the liver, and high levels of serum or urine 5-hydroxyindolacetic acid and serum chromogranin A were found to be at higher risk of developing carcinoid crisis.
#51 Carcinoid Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK448096/
Excess serotonin causes increased gastrointestinal motility and hypersecretion, leading to diarrhea, one of the hallmarks of carcinoid syndrome. […] Carcinoid syndrome presents a range of symptoms due to the vasodilatory effects of biologically active amines, peptides, and prostaglandins. […] The management of carcinoid syndrome centers on suppressing biogenic amine release and reducing tumor burden using multiple modalities. […] Somatostatin analogs (SSA) are the cornerstone of medical management. […] PRRT is a targeted systemic treatment for advanced neuroendocrine tumors that express somatostatin receptors, utilizing radiolabeled somatostatin analogs (eg, lutetium-177) to deliver localized ionizing radiation to tumor cells. […] Carcinoid crisis is a potentially life-threatening complication characterized by severe hemodynamic instability, flushing, bronchoconstriction, and hypotension, often triggered by surgery, anesthesia, or tumor necrosis.
#52 Carcinoid syndrome: update on the pathophysiology and treatment | Clinics
https://www.elsevier.es/en-revista-clinics-22-articulo-carcinoid-syndrome-update-on-pathophysiology-S1807593222011310
5-HT secreted by NETs appears to play a central role in MF. A recent study demonstrated a significant association of MF with elevated urinary 5-HIAA levels, suggesting a potential causal relationship. […] The diagnosis of CS requires the combination of carcinoid symptoms and evidence of elevated levels of 5-HIAA in a 24-h urine sample. […] The main pillar of treatment for CS is the use of somatostatin analogues, such as octreotide and lanreotide.
#53 SciELO Brazil – Carcinoid syndrome: update on the pathophysiology and treatment Carcinoid syndrome: update on the pathophysiology and treatment
https://www.scielo.br/j/clin/a/TJBtjyHRK9DFDhWKP4dhK4J/
Despite the strong evidence of 5-HT involvement in the development of carcinoid heart disease, a significant proportion of patients with elevated plasma levels of 5-HT do not develop this condition, which suggests that there are other biochemical or genetic mechanisms involved. […] 5-HT secreted by neuroendocrine tumors appears to play a central role in mesenteric fibrosis. A recent study demonstrated a significant association of mesenteric fibrosis with elevated urinary 5-HIAA levels, suggesting a potential causal relationship. […] The diagnosis of carcinoid syndrome requires the combination of carcinoid symptoms and evidence of elevated levels of 5-HIAA in a 24-h urine sample. […] The main pillar of treatment for carcinoid syndrome is the use of somatostatin analogues, such as octreotide and lanreotide. […] However, studies suggest that their use does not lead to regression of carcinoid syndrome or prevent its occurrence.
#54 Carcinoid Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK448096/
Excess serotonin causes increased gastrointestinal motility and hypersecretion, leading to diarrhea, one of the hallmarks of carcinoid syndrome. […] Carcinoid syndrome presents a range of symptoms due to the vasodilatory effects of biologically active amines, peptides, and prostaglandins. […] The management of carcinoid syndrome centers on suppressing biogenic amine release and reducing tumor burden using multiple modalities. […] Somatostatin analogs (SSA) are the cornerstone of medical management. […] PRRT is a targeted systemic treatment for advanced neuroendocrine tumors that express somatostatin receptors, utilizing radiolabeled somatostatin analogs (eg, lutetium-177) to deliver localized ionizing radiation to tumor cells. […] Carcinoid crisis is a potentially life-threatening complication characterized by severe hemodynamic instability, flushing, bronchoconstriction, and hypotension, often triggered by surgery, anesthesia, or tumor necrosis.
#55 The role of serotonin inhibition within the treatment of carcinoid syndrome in: Endocrine Oncology Volume 3 Issue 1 (2023)
https://eo.bioscientifica.com/view/journals/eo/3/1/EO-22-0077.xml
Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning NETs for several decades. […] Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumour growth via the somatostatin receptor 2 (SSTR2). Direct antiproliferative effects occur through the activation of Src homology 2 domain phosphatase-1 and Src homology 2 domain phosphatase-2, which through a phosphorylation pathway, dephosphorylates phosphatidylinositol 3-kinase and extracellular signal-regulated protein kinases 1 and 2, leading to impaired cell proliferation. […] Telotristat ethyl (TE) is a novel, oral, tryptophan hydroxylase inhibitor. It has a high-molecular-weight and acidic moieties, inhibiting the drug from crossing the blood-brain barrier, thus creating a physiological selectivity for TPH1; TE produces a significant reduction in 5-HT concentration in the intestine without impacting the concentration of 5-HT in the CNS. […] The study showed 75% of patients on TE experienced a significant improvement in bowel movement frequency by 12 weeks. In addition, improvements in stool form were observed.
#56 The role of serotonin inhibition within the treatment of carcinoid syndrome in: Endocrine Oncology Volume 3 Issue 1 (2023)
https://eo.bioscientifica.com/view/journals/eo/3/1/EO-22-0077.xml
Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning NETs for several decades. […] Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumour growth via the somatostatin receptor 2 (SSTR2). Direct antiproliferative effects occur through the activation of Src homology 2 domain phosphatase-1 and Src homology 2 domain phosphatase-2, which through a phosphorylation pathway, dephosphorylates phosphatidylinositol 3-kinase and extracellular signal-regulated protein kinases 1 and 2, leading to impaired cell proliferation. […] Telotristat ethyl (TE) is a novel, oral, tryptophan hydroxylase inhibitor. It has a high-molecular-weight and acidic moieties, inhibiting the drug from crossing the blood-brain barrier, thus creating a physiological selectivity for TPH1; TE produces a significant reduction in 5-HT concentration in the intestine without impacting the concentration of 5-HT in the CNS. […] The study showed 75% of patients on TE experienced a significant improvement in bowel movement frequency by 12 weeks. In addition, improvements in stool form were observed.
#57 The role of serotonin inhibition within the treatment of carcinoid syndrome in: Endocrine Oncology Volume 3 Issue 1 (2023)
https://eo.bioscientifica.com/view/journals/eo/3/1/EO-22-0077.xml
Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning NETs for several decades. […] Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumour growth via the somatostatin receptor 2 (SSTR2). Direct antiproliferative effects occur through the activation of Src homology 2 domain phosphatase-1 and Src homology 2 domain phosphatase-2, which through a phosphorylation pathway, dephosphorylates phosphatidylinositol 3-kinase and extracellular signal-regulated protein kinases 1 and 2, leading to impaired cell proliferation. […] Telotristat ethyl (TE) is a novel, oral, tryptophan hydroxylase inhibitor. It has a high-molecular-weight and acidic moieties, inhibiting the drug from crossing the blood-brain barrier, thus creating a physiological selectivity for TPH1; TE produces a significant reduction in 5-HT concentration in the intestine without impacting the concentration of 5-HT in the CNS. […] The study showed 75% of patients on TE experienced a significant improvement in bowel movement frequency by 12 weeks. In addition, improvements in stool form were observed.
#58 Carcinoid Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK448096/
Excess serotonin causes increased gastrointestinal motility and hypersecretion, leading to diarrhea, one of the hallmarks of carcinoid syndrome. […] Carcinoid syndrome presents a range of symptoms due to the vasodilatory effects of biologically active amines, peptides, and prostaglandins. […] The management of carcinoid syndrome centers on suppressing biogenic amine release and reducing tumor burden using multiple modalities. […] Somatostatin analogs (SSA) are the cornerstone of medical management. […] PRRT is a targeted systemic treatment for advanced neuroendocrine tumors that express somatostatin receptors, utilizing radiolabeled somatostatin analogs (eg, lutetium-177) to deliver localized ionizing radiation to tumor cells. […] Carcinoid crisis is a potentially life-threatening complication characterized by severe hemodynamic instability, flushing, bronchoconstriction, and hypotension, often triggered by surgery, anesthesia, or tumor necrosis.
#59 Gastrointestinal Neuroendocrine Tumors and Carcinoid Syndrome – Endocrine and Metabolic Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/gastrointestinal-and-pancreatic-neuroendocrine-tumors-nets/gastrointestinal-neuroendocrine-tumors-and-carcinoid-syndrome
Resection of primary gastrointestinal and bronchial NETs in patients with carcinoid syndrome is often curative. […] For patients with hepatic metastases, surgical debulking of the tumor, while not curative, may relieve symptoms and, in certain instances, prolong survival. […] Standard chemotherapy and radiation therapy are not effective, but other treatments such as everolimus and peptide receptor radionuclide therapy (PRRT) with 177-lutetium may be helpful.