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Main symptoms are flushing, diarrhea and bronchospasm.
Diarrhea and flushing, occurring in approximately 10% of small bowel carcinoids.
Advanced midgut NETs are known to produce vasoactive substances such as serotonin, prostaglandins, kallikrein, and substance P.
These vasoactive agents are metabolized in the liver.
In the presence of hepatic, neural, or bone NET metastasis, these agents are released directly into the systemic circulation, bypassing hepatic degradation and ultimately causing carcinoid syndrome.
Although, as noted, carcinoid syndrome is associated predominantly with midgut NETs can occur with thymic, bronchial, and pancreatic NETs.
20% 20 to 30% of patients with NETs may have a functional syndrome.
Carcinoid syndrome symptoms:
flushing
diarrhea
asthma or wheezing
congestive heart failure (CHF)
abdominal cramping
peripheral edema
heart palpitations
A carcinoid crisis presents with profound flushing, bronchospasm, tachycardia, and widely and rapidly fluctuating blood pressure with large amounts of hormone are acutely secreted.
Diarrhea and flushing are the most common manifestations, and broncospasm is seen less frequently.
Hormone release in carcinoid tumors is occasionally triggered by diet, alcohol, surgery, chemotherapy, embolization therapy or radiofrequency ablation.
Diarrhea is attributable to serotonin, which stimulates serotonin 2A receptors.
Flushing is thought to be triggered by bradykinin, histamine, and substance P, and other substances.
Diarrhea with NET‘s can be multifactorial: exocrine pancreatic insufficiency, short bowel syndrome, bacterial overgrowth, and biled acid malabsorption.
Fibrosis, arthropathy and increased skin pigmentation may be seen.
Associated with liver metastases that allow vasoactive substances to reach the right side of the heart without being inactivated by first pass metabolism of the liver.
Carcinoid heart disease is seen in up to 50% of patients with carcinoid syndrome.
The most serious complication of carcinoid tumors is the development of plaque like fibrous deposits, most commonly that form on cardiac valves on the right side.
Cardiac valves on the left side, are less likely to be affected, because the lungs can activate vasoactive compounds.
Valvula involvement on the left side and carcinoid syndrome can occur in patients with patent foramen ovale.
Typical findings in carcinoid heart disease is right sided heart failure, lower extremity edema, cardiac murmurs, jugular venous distention, palpable hepatomegaly, and exertional dyspnea with the affects predominantly of right heart right sided heart valve disease.
All patients with carcinoid syndrome, and patient with serotonin overproduction should be screened with echocardiography with particular attention to the right sided heart valves.
Carcinoid syndrome occurs in 8-35% of patients with such tumors and occurs mostly in patients with hepatic metastases.
Incidence increasing in NETs ( Neuroendocrine tumors)
Carcinoid syndrome associated with a shorter overall median survival compared to patients with NETs without the syndrome.
Most cases of carcinoid syndrome likely to occur in patients with tumors that originate in the small intestine or appendix.
Metabolic products released by intestinal carcinoid or rapidly destroyed by blood and liver enzymes, and explains why carcinoid syndrome is not seen unless hepatic metastasis are present.
Metastases release metabolic products directly into the systemic circulation and cause flushing, and diarrhea.
The prevalence of pre-treatment carcinoid syndrome symptoms among patients in a phase 3 clinical trial included: bowel movement related issues 97%, Flushing 86%, abdominal pain 63%. And 80% head meaningful reduction in quality of life and work.o
Diarrhea associated with carcinoid syndrome can be profound, with more than 10 bowel movements per day.
Diarrhea is typically secretory in nature, with over 1 liter of watery stool per day.
Diarrhea persists despite fasting.
Almost all carcinoid tumors make serotonin, prostaglandins, 5-HTP, substance P, kallikrein, histamine, dopamine, and neurotensin (van der Lely AJ).
Symptoms of carcinoid syndrome are in a large part related to the secretion of serotonin.
Chromagranin A in endocrine tissues and its measurement is considered the gold standard biochemical test for the diagnosis of carcinoid and neuroendocrine tumors.
Occurs in up to 18% or more of patients with carcinoid tumors, and midgut tumors account for 60-87% of carcinoid syndrome.
More than 50% of patients develop carcinoid heart disease.
Diarrhea occurs in up to 80% of cases.
Heart lesions are found predominantly on the right side with plaques composed of fibrous tissue, smooth muscle cells, extra cellular matrix and an endocardial cell layer.
The tricuspid valve is typically involved, and in some cases the valve needs to be replaced.
Heart disease manifests with endocardial thickening that results in retraction and fixation of right sided valves leading to valve dysfunction and heart failure.
Heart disease associated with congestive heart failure has a poor prognosis.
Hepatic resection of lesions can improve the survival of patients with carcinoid heart disease by decreasing progression of cardiac lesions.
Concentrations of urinary 5-HIAA levels higher in patients with carcinoid heart disease than those without cardiac disease.
The presence of the carcinoid syndrome confers a median survival ranging from less than 1 year to 38 months.
Develops when the carcinoid tumor metastasizes and releases serotonin and other vasoactive substances into the circulation.
Symptoms are caused by upregulated release of serotonin and other peptide hormones that involve smooth muscle control.
Serotonin can interact with receptors on fibroblasts and likley leads to valvular fibrosis seen in ling standing carcinoid syndrome.
Serotonin may cause fibrosis of the bowel, known as mesenteric fibrosis, and can lead to bowel obstruction.
In Carcinoid syndrome tryptophan is preferentially oxidized to serotonin and not metabolized to niacin.
The body has less available tryptophan to convert to niacin.
Median survival of 38 months from the first episode of flushing in only 25% of such patients live more than six years (Davis Z).
Urinary 5-HIAA in excess of 150 mg24 hours or inoperable tumors are associated with a median survival of only 13 months (Davis Z).
Urinary 5-HIAA level is used as a proxy for the serum serotonin level; serum serotonin, is metabolized by the liver to a terminal metabolite, 5-HIAA which is cleared by the kidneys.
Carcinoid syndrome is seen in less than 20% of patients with intestinal neuroendocrine neoplasms.
Carcinoid crisis refers to a perioperative with stress associated endocrine emergency manifested by circulatory collapse triggered by an acute release of vasoactive amines into systemic circulation: triggers include catecholamine exposure, anesthetic agents, physical stress, infections, and manipulation of tumors.
Somatostatin analogs and alpha interferon are successful in treating symptoms without causing tumor regression.
Traditional approach to this syndrome is to initiate treatment with a somatostatin analogue.
Approximately 60% of patients are responsive to initial somatostatin therapy but they do lose effect overtime, resulting in refractory symptoms.
Somatostatin analogues act on somatostatin receptor subtype 2 of tumor cell, blocking hormone release.
With carcinoid syndrome octreotide can control diarrhea and flushing in about 40-50% of patients.
Octreotide can improve the symptoms of carcinoid in up to 88% of patients (Kvols EK et a).
Octreotide acts as an anti-secretory agent that inhibits the secretion of multiple hormones of neuroendocrine tumors.
Lanreotide is a somatostatin analogue available as a long-acting subcutaneous injection and had similar rates of symptom control and reduction in biochemical markers as octreotide (O’toole D et al).
Telotristat ethyl, a tryptophan hydroxylase inhibitor associated with significan reduction in symptoms.
Telotristat ethyl in combination with somatostatin analogue therapy improves carcinoid syndrome diarrhea control.
Telotristat is an oral medication in combination with octreotide, that inhibits the conversion of tryptophan to serotonin.
Telotristat dose 250 mg TID with food.
Octreotide should be given 30 minutes after Telotristat to avoid decreased concentrations of Telotristat.