Carcinoid syndrome

5-hydroxytryptamine in advemced ctucinoid syndrome maybe so great that as much tis 60% of the body s tryptophtm metabolism proceeds by this pathway, comptued with about 1% under normed conditions. A significemt number of 

Carcinoid is a tumor of the enterochromaffin cells that normally synthesize 5-hydroxytrytophan and 5-hydroxytryptamine. The carcinoid syndrome is seen when there are significant metastases of the primary tumor in the liver. It is characterized by increased gastrointestinal motility and diarrhea, as well as by regular periodic flushing. These symptoms can be attributed to systemic release of large amounts of serotonin and can be controlled with inhibitors of tryptophan hydroxylase, such as p-chlorophenylalanine. The synthesis of 5-hydroxytryptamine in advanced carcinoid syndrome may be so great that as much as 60% of the body s tryptophan metabolism proceeds by this pathway, compared with about 1% under normal conditions. A significant number of 

---

Mast cell or basophil leukemia Carcinoid syndrome Thyroid carcinoma Pheochromocytoma... 

A number of genetic diseases that result in defects of tryptophan metabolism are associated with the development of pellagra despite an apparently adequate intake of both tryptophan and niacin. Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan, resulting in large losses due to intestinal malabsorption and failure of the renal resorption mechanism. In carcinoid syndrome there is metastasis of a primary liver tumor of enterochromaffin cells which synthesize 5-hydroxy-tryptamine. Overproduction of 5-hydroxytryptamine may account for as much as 60% of the body s tryptophan metabolism, causing pellagra because of the diversion away from NAD synthesis. 

Carcinoid syndrome, anemias, systemic lupus erythematosus... 

Malignant carcinoid tumors, a symptom of carcinoid syndrome, presented a therapeutic challenge for many years until the introduction of interferon treatment in 1982 by Oberg and Eriksson [51]. They reported that 47 out of 111 patients (42%) treated with interferon- / (median dose of 6 mega-units (MU) of interferon-a, five... 

Endocrine system (Cushing s disease, Addison s disease, carcinoid syndrome, diabetes, hyperthyroidism. Grave s disease, hypothyroidism)... 

Serotonin is an important neurotransmitter, a local hormone in the gut, a component of the platelet clotting process, and is thought to play a role in migraine headache. Serotonin is also one of the mediators of the signs and symptoms of carcinoid syndrome, an unusual manifestation of carcinoid tumor, a neoplasm of enterochromaffin cells. In patients whose tumor is not operable, a serotonin antagonist may constitute a useful treatment. 

Hydroxylation at C5 is the rate-limiting step and can be blocked by p-chlorophenylalanine (PCPA fenclonine) and by p-chloroamphetamine. These agents have been used experimentally to reduce serotonin synthesis in carcinoid syndrome but are too toxic for clinical use. 

Serotonin has a small direct stimulant effect on bronchiolar smooth muscle in normal humans, probably via 5-HT2A receptors. It also appears to facilitate acetylcholine release from bronchial vagal nerve endings. In patients with carcinoid syndrome, episodes of bronchoconstriction occur in response to elevated levels of the amine or peptides released from the tumor. Serotonin may also cause hyperventilation as a result of the chemoreceptor reflex or stimulation of bronchial sensory nerve endings. 

Serotonin also constricts veins, and venoconstriction with increased capillary filling appears to be responsible for the flush that is observed after serotonin administration or release from a carcinoid tumor. Serotonin has small direct positive chronotropic and inotropic effects on the heart, which are probably of no clinical significance. However, prolonged elevation of the blood level of serotonin (which occurs in carcinoid syndrome) is associated with pathologic alterations in the endocardium (subendocardial fibroplasia), which may result in valvular or electrical malfunction. 

Ketanserin (not available in USA) Competitive blockade at 5- 2 receptors Prevents vasoconstriction and bronchospasm of carcinoid syndrome Hypertension carcinoid syndrome associated with carcinoid tumor Oral duration 12-24 h Toxicity Hypotension Interactions Data not available... 

Of 24 patients with hepatocellular carcinoma receiving octreotide LAR, 11 had mild diarrhea (32). The effect of octreotide on bowel transit appears to be variable. In some patients, such as those with carcinoid syndrome, it is useful for the management of diarrhea. 

Like histamine, serotonin is widely distributed in nature, being found in plant and animal tissues, venoms, and stings. It is an indoleethylamine formed in biologic systems from the amino acid L-tryptophan by hydroxylation of the indole ring followed by decarboxylation of the amino acid (Figure 16-3). Hydroxylation at C5 is the rate-limiting step and can be blocked by p-chlorophenylalanine (PCPA fenclonine) and by /i-chloroamphetamine. These agents have been used experimentally to reduce serotonin synthesis in carcinoid syndrome. 

Several physiological conditions (e.g. Hartnup disease and malignant carcinoid syndrome) can lead to niacin deficiency. 

In Hartnup disease tryptophan absorption is impaired and in malignant carcinoid syndrome tryptophan metabolism is altered resulting in excess serotonin synthesis. 

Rubin, J. Ajani, J. Schirmer, W. Venook, A.P. Bukowski, R. Pommier, R. Saltz, L. Dandona, P. Anthony, L. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in mahgnant carcinoid syndrome. J. Clin. Oncol. 1999,17 (2), 600-606. 

Restrictive cardiomyopathy due to endocardial fibrosis occurred in a 35-year-old woman 5 months after she had started to take fenfluramine 10 mg tds and phentermine 15 mg/day (7). The endocardial findings strongly resembled the valvular lesions associated with the use of fenfluramine-phentermine. Endocardial and valvular fibrosis associated with anorectic drugs is strikingly similar to the plaque material found in patients with carcinoid syndrome and those exposed to methysergide, and all possibly arise from a common mechanism. 

---