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Flushing Causes Pt 2 (Read 12031 times)
Lisa
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Volta Redonda, RJ Brazil
Flushing Causes Pt 2
01/06/11 at 03:40:51
 
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Note:  This is information which came from the Cleveland Clinic's website, however this informative page was removed from the internet.   Although the information regarding Carcinoid Syndrome and Systemic Mastocytosis are somewhat antiquated and new research has given more understanding to both diseases, the information contained within this article is still valid and worth reading and perhaps passing on to your doctors for their aide.  However, in regards to the information on mastocytosis as to it's diagnostic procedures and forms, there is more recent research on this forum which is of better use for doctors.




Carcinoid Syndrome:
"Carcinoid syndrome" describes the manifestations of carcinoid tumors: flushing, bronchoconstriction, gastrointestinal hypermotility, and cardiac disease. Carcinoid tumors are neuroendocrine tumors that derive from a primitive stem cell that may differentiate into any of a variety of adult endocrine-secreting cells, producing a variety of peptides, hormones, and neurotransmitters. The annual incidence is 1.5 per 100,000 population.9 The average age of patients is 50 years, and there is no gender predominance.10
Carcinoid syndrome occurs in about 10% of patients with these tumors.10 In 75% of patients, episodes of severe flushing are precipitated by exercise, alcohol, stress, and certain foods (spices, chocolate, cheese, avocados, plums, walnuts,1 red sausage, and red wine). With time the flushing may appear without provocation.9 The character of the flush differs depending upon the site of origin of the tumor (Figures 1 and 2). Tumors of the foregut (stomach, lung, pancreas) are associated with a bright-red "geographic" flush of a more sustained duration, as well as lacrimation, wheezing, sweating, and a sensation of burning. In ileal tumors, the flush is patchier and more violaceous, intermingled with areas of pallor, and does not last as long. Flushing of either type may be associated with facial edema that may persist and lead to telangiectasia and even facial rosacea. With extensive disease, one can also see pellagra-like skin lesions. (These result from excessive utilization of tryptophan by the carcinoid tumor, leaving little for the daily niacin requirement). These lesions include hyperkeratosis; xerosis; scaling of the legs, forearms, and trunk; angular cheilitis; and glossitis (Figure 3). Seventy percent of patients also have watery diarrhea, and 35% develop right-sided endocardial fibrosis leading to congestive heart failure. Diarrhea and other gastrointestinal manifestations may precede or coexist with the flushing.5

Ninety-five percent of all carcinoids are found in the appendix, rectum, or small intestine.9 The remainder arise outside of the intestinal tract (ovary, testis). In general, the larger the primary tumor, the greater the likelihood of metastasis, which provides prognostic implications.9 Carcinoids of the appendix and rectum rarely present with the carcinoid syndrome. Forty to 50% of patients with carcinoids of the small intestine or proximal colon have manifestations of the carcinoid syndrome.10 Tumors that secrete their hormonal product into the portal venous system do not cause flushing because the released amines are inactivated by the liver. In contrast, liver metastases may escape hepatic inactivation and deliver their product directly into the systemic circulation and hence cause flushing.9 Pulmonary or ovarian carcinoids release pharmacological products directly into the venous circulation, bypassing the portal system, and can therefore cause symptoms without metastasizing to the liver.1,10

Pathophysiology
The flushing seen with foregut carcinoids is due to release of histamine. Flushing seen with ileal carcinoids cannot be explained solely by the production of serotonin.1 Serotonin may or may not be released into the circulation during flushing, and intravenous infusion of serotonin does not cause flushing. Foregut carcinoids do not generally secrete serotonin but, instead, its precursor, 5-hydroxytryptamine. Screening should therefore seek this product if the other metabolites are not elevated.9 Other mediators that have been proposed include prostaglandins and tachykinins. Tachykinins are believed to be mediators of the flushing in tumors of the midgut. They exert vasodilation and contraction of various types of smooth muscle. These peptides include substance P, substance K, and neuropeptide K. Urine
excretion of histamine is usually increased in patients who have gastric carcinoid (Table 3).9

Diagnosis
Clinical diagnosis is not difficult in patients with flushing episodes associated with systemic symptoms (diarrhea, wheezing, and weight loss) and hepatomegaly. It is more difficult in patients who have occasional flushing and no associated symptoms.1 Only when there is reasonable clinical suspicion should biochemical testing be done, and localization studies must be reserved for those cases proven biochemically.10 When in doubt, a carcinoid flush can be provoked by alcohol ingestion (4 mL of 45% ethanol) or the infusion of 6 µg noradrenaline, an effect that can be blocked by phentolamine (5 to 15 mg intravenously). Calcium gluconate, 10 to 15 mg/kg, administered intravenously over 4 hours, may produce a flush mimicking a spontaneous attack.5 Epinephrine reverses flushing in patients with mastocytosis but provokes flushing in patients with the carcinoid syndrome. The procedure should only be performed in a controlled environment. A 1 µg/mL solution of epinephrine in normal saline is administered by intravenous bolus beginning with an initial dose of 0.05 µg. The dose is doubled at intervals of 10 minutes until flushing appears or a until a maximum of 6.4 µg is given. When flushing occurs, it usually begins within 60 seconds after epinephrine administration and dissipates after 3 or 4 minutes.10

The diagnosis should be confirmed by determining urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin, which is normally 2 to 10 mg (10 to 50 µmol) per 24 hours.5 A value of more than 150 µmol/24 hours (30 mg/24 hours) usually confirms the diagnosis, and in carcinoid syndrome it is often above 40 mg per day.5 This test has a sensitivity of 50% and a specificity of up to 100%. The degree of elevation of 5-HIAA does not always correlate with the severity of flushing.9 Excretion fluctuates, so that repeated measurements may be necessary. Some patients with carcinoid may lack the metabolic machinery to convert serotonin to 5-HIAA, so they have high blood levels of serotonin but normal urinary 5-HIAA.5 Dietary factors may cause confusion; the patient should therefore receive a diet free of the culprit items (Table 4) for 3 days before the urine collection is made. Although the levels of serotonin in patients with tumors usually far exceed those found after food ingestion, this precaution helps to exclude carcinoid in individuals with borderline-high 5-HIAA levels.9 Measuring blood serotonin is helpful when urinary 5-HIAA is equivocal. Patients with carcinoid syndrome have very high blood levels of serotonin. Measurement of serotonin and its metabolites permits the detection of 84% of neuroendocrine tumors. Even carcinoids that predominantly secrete 5-hydroxytryptophan are associated with increased urinary excretion of 5-HIAA because the released 5-hydroxytryptophan is converted to serotonin in other tissues and is subsequently metabolized to 5-HIAA.9 Chromogranin A, a peptide co-secreted with serotonin, is elevated in most patients with carcinoid tumors. In the evaluation of flushing with an equivocal 24-hour urinary 5-HIAA, a normal plasma chromogranin A value suggests nonendocrine causes. This test is sensitive but not specific, and its predictive value in carcinoid is still uncertain.10 Flushing was associated with a rise in circulating substance P in 80% of patients with gastric carcinoid. Neurokinin A levels are elevated in certain patients (Tables 4 and 5).9

Table 4:

Factors That Can Precipitate Flushing In the Carcinoid Syndrome
•      Foods and Beverages
o      Hot food/beverage
o      Spicy food
o      Chocolate
o      Cheeses
o      Tomatoes
o      Avocados
o      Red plums
o      Walnuts
o      Eggplant
o      Alcohol
•      Emotional Stress
•      Valsalva maneuver
o      Straining
o      Vigorous coughing
•      Sudden direct pressure on a large carcinoid tumor


Management
Corticosteroids, phenothiazines, and bromocriptine have been effective in the treatment of patients with bronchial carcinoid tumors. The mechanism of action of these agents is unknown. Cyproheptadine, a serotonin antagonist, may control the flushing. Methysergide can control the diarrhea but has no effect on flushing. Combined administration of H1 and H2 receptor antagonists may prevent attacks of flushing in patients with foregut carcinoid tumors that produce histamine.10 Alpha-interferons may control symptoms of carcinoid syndrome and produce objective biochemical responses (greater than 50% suppression of 5-HIAA) that have a median duration of about 4 weeks.10 Since catecholamines are known to precipitate attacks, a trial of clonidine is worthwhile. Somatostatin is a potent antagonist of the flushing reaction associated with both gastric and ileal carcinoid tumors but has a short half-life. The somatostatin analogue octreotide has a much longer half-life, making subcutaneous therapy possible. It must be given by subcutaneous injection one to three times a day and should be titrated in increments of 50 µg every 8 hours.10 Octreotide lowers plasma levels of serotonin and tachykinins and relieves both flushing and diarrhea. Amelioration of these manifestations is accompanied by a marked reduction in the urinary excretion of 5-HIAA.10 Lanreotide, a long acting analogue of somatostatin administered intramuscularly every 14 days, is effective at controlling the flushing of carcinoids.11,12 A depot form of octreotide (Sandostatin LAR) has been shown to control flushing at a dose of 20 mg intramuscularly every month.13 Flushing may relapse with continued treatment.9 The patient should receive an adequate niacin supplement (nicotinamide rather than nicotinic acid, since the latter causes flushing) and should avoid foods, agents, and activities that precipitate symptoms.5

In some patients, failure of medical treatment may necessitate carrying out hepatic artery embolization. This treatment is based upon the dependence of metastatic malignant tissue but not healthy liver parenchyma on an intact hepatic arterial blood supply. Anti-tumor chemotherapy remains experimental. Alpha-interferon causes symptomatic relief accompanied by lowering of urinary 5-HIAA. (For more discussion on the treatment of carcinoid tumors, see Carcinoid Tumor.)

Prognosis
About one-fifth of patients with the carcinoid syndrome undergo a protracted course. In the remainder, deterioration can be rapid. The mean survival is about 8 years with some surviving up to 20 years. Mean survival is 36 months after the first flushing episode.9

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Mastocytoses:

Etiology
Mastocytoses are benign proliferative disorders of the reticuloendothelial system and familial cases have been reported. Mastocytoses are due to a hyperplastic rather than a neoplastic process. They are often self-limited, especially in childhood (Table 6). Mast cells possess the enzyme histidine decarboxylase which enables them to synthesize and store histamine. Other preformed mediators include tryptase, chymase, and carboxypeptidase. Serotonin has not been detected in human mast cells.14

Histopathology
There are increased numbers of normal-looking mast cells in the dermis. These cells may be predominantly perivascular or may show a nodular distribution. The epidermis is normal, except for increased melanization.

Biochemical Markers
Symptoms of mastocytosis are mainly the result of release of products of mast-cell activation. Plasma histamine levels are frequently raised in patients with systemic symptoms, and elevated urinary excretion of histamine and its metabolite methyl imidazole acetic acid (MIAA) can also be seen. Plasma tryptase levels can also be elevated. Prostaglandin D2 (PGD2) is another product of mast-cell activation. Urinary excretion of this substance and its major metabolites can be elevated several-fold in patients with mastocytoses. Urine should be collected within a few hours of an attack.14

Clinical Presentation
Episodic bright-red flushing occurs either spontaneously or after rubbing the skin or exposure to alcohol or mast-cell degranulating agents. Flushing attacks may be accompanied by headache, dyspnea and wheezing, palpitations, abdominal pain, diarrhea, and syncope and may closely resemble the flushing episodes of the carcinoid syndrome, especially the foregut variety, which are also mediated by histamine. Rosacea may develop rarely. PGD2 might be associated with the symptoms of flushing and diarrhea.14 The flushing of cutaneous mastocytosis typically lasts more than 30 minutes, unlike the typical carcinoid flush which lasts less than 10 minutes.5 In urticaria pigmentosa, the diagnosis is established by demonstrating that gentle rubbing of the lesional skin causes local itching, redness, and whealing (Darier's sign). This reaction is due to local histamine release. Darier's sign may also be demonstrated in nonlesional skin. Confirmation of the diagnosis is obtained by skin biopsy. In patients with systemic symptoms, bone-marrow biopsy and liver and spleen scans are usually performed. Bone scans should only be carried out in the presence of localized bone symptoms.5,14

Treatment
Treatment of nonlocalized forms of mastocytosis is mainly symptomatic. Patients should avoid known histamine-degranulating agents. Antihistamines remain the preferred treatment for most patients with uncomplicated urticaria pigmentosa. Human skin blood vessels possess H1 and H2 receptors, which are involved in both vasodilation and increased vascular permeability evoked by histamine.  Thus, combination treatment with an H1 antihistamine (hydroxyzine, 10 to 20 mg) and H2 antihistamine (cimetidine, 200 to 500 mg) is logical and sometimes effective at controlling the flushing episodes. Oral administration of the mast-cell stabilizing agent disodium cromoglycate has proved effective in some patients. The drug does not decrease urinary excretion of histamine and the histamine metabolite MIAA. Some experts recommend using this agent only in patients with systemic mastocytosis suffering fram gastrointestinal symptoms. Photochemotherapy has been reported to cause symptomatic relief as well as objective reduction in the population of mast cells and the urinary excretion of MIAA.14

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Medullary Thyroid Carcinoma:
The range of substances secreted by medullary carcinoma of the thyroid is considerable, whether sporadic or familial. Flushing is the most common symptom after diarrhea. Occurring in one-third of the patients with diarrhea, there is pronounced episodic flushing, which as in the carcinoid syndrome may be induced by alcohol ingestion. Calcitonin-gene related peptide, which is an extremely powerful peripheral vasodilator, is the most likely mediator that causes flushing.5 The other possible explanation is that calcitonin stimulates prostaglandins which in turn cause the symptoms.12

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Harlequin Syndrome:
This describes hemifacial flushing and sweating sometimes associated with warmth and anhidrosis of the contralateral arm and leg (Figure 4). This may be induced by exercise. The suggested etiology is a lesion involving both preganglionic or postganglionic cervical sympathetic fibers and parasympathetic neurons of the ciliary ganglion.15 Harlequin syndrome has been described in patients with a contralateral lung cancer invading the spine, Pancoast's syndrome, and Horner's syndrome.5

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Auriculotemporal Nerve Syndrome  (Frey's Syndrome):
This syndrome usually manifests as immediate unilateral or bilateral flushing and/or sweating in the distribution of the auriculotemporal nerve in response to gustatory or tactile stimuli. In adults, this syndrome is a well recognized sequela of parotid surgery, trauma, or infection. It occurs rarely in children, most often noted after the introduction of solid food. The flushing is often attributed erroneously to food allergy. It typically begins at 2 to 6 months of age when solid foods, mostly fruit, are introduced. Occurring within a few seconds of eating, it has a peculiar distribution in a triangular area that extends fram the tragus of the ear to the midpoint of the cheek. It is not associated with sweating and persists for 20 to 60 minutes. The flushing continues to occur for up to 5 years. In adults, gustatory sweating is the predominant feature of auriculotemporal nerve syndrome; flushing happens less often. Half of the pediatric patients with this symptom were delivered with forceps assistance which possibly causes trauma to the nerve. The likely mechanism is misdirection of parasympathetic fibers along sympathetic pathways during the nerve regeneration that follows trauma. This may account for erythema when eating. The emergence of symptoms several months after the proposed trauma (usually 3 to 6 months) is probably related to the time required for nerve regeneration, and it is possible that vigorous chewing causes intense stimulation of the parotid gland. Auriculotemporal nerve syndrome is benign in infants and does not tend to worsen. Furthermore, the severity of the flushing tends to diminish with age in most patients. The physician can reassure parents and avoid unnecessary testing and maneuvers16 (Figure 5). A similar syndrome can develop after facial herpes zoster.17

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Flushing with Pseudocarcinoid Syndrome in Secondary Male Hypogonadism:
A series of three male patients with secondary hypogonadism has been described where flushing was associated with elevated 24-hour urine 5-HIAA. Flushing disappeared and 5-HIAA levels normalized after starting testosterone enanthate treatment. Male patients with flushing and increased urinary 5-HIAA levels should undergo assessment for hypogonadism after screening for carcinoid tumor.18
Treatments that lower serum testosterone, such as orchiectomy or luteinizing hormone-releasing hormone analogs, cause hot flushes in over half of men. Lack of regulatory feedback in the hypothalamus due to circulating serum testosterone is the presumed mechanism. Most often, hot flushes are only mildly bothersome and can be tolerated without the need for treatment. However, if flushes are particularly annoying or problematic, treatment should be offered. Small doses of diethylstilbestrol are effective in relieving hot flushes but cause gynecomastia. Megestrol acetate, at a dose of 20 mg bid, completely eliminates hot flushes in most men, and the dose can be progressively lowered in some.19


To be Continued......
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« Last Edit: 01/06/11 at 10:59:17 by Lisa »  

Don´t forget, there is so much more to life than being sick!
 
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