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Prevalence Evaluation
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Flushing describes
episodic attacks of redness of the skin together with a sensation of warmth
or burning of the face, neck, and less frequently the upper trunk and
abdomen. Flushing can be an exaggeration of a physiological process or a manifestation of a serious condition that needs to be identified and treated. A biochemical work-up of every case of flushing is neither practical nor cost-effective; in this chapter, the author will present guidelines that will help determine when a work-up is warranted. |
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The prevalence of flushing has not been determined. |
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Redness of the skin may be due to an increased amount of saturated hemoglobin, an increase in the diameter or actual number of skin capillaries, or a combination of these factors.2 Flushing is due to increased blood flow through the skin, causing warmth, and because of engorgement of the subpapillary venous plexus, redness. The vasodilatation of flushing may be due to a direct action of a circulatory vasodilator substance, for example histamine, or it may be caused by changes in the neurological control of the cutaneous vasculature in the affected areas. In the face, neck, and upper trunk, where flushing is most frequent, the neurological control of vascular tone is predominantly exerted by autonomic vasodilator nerve fibers. These fibers are found in somatic nerves supplying the affected skin, including the trigeminal nerve. Since autonomic nerve fibers also supply eccrine sweat glands, neurally activated flushing is frequently associated with sweating (wet flushing) as opposed to flushing due to circulating vasodilator mediators which frequently does not involve sweating (dry flushing). The presence or absence of sweating has therefore been proposed as a clinical guide to the mechanisms of flushing, although in practice this is not always reliable. Examples of wet flushing are physiological flushing and menopausal flushing. An example of dry flushing is niacin-provoked flushing.1 The diameter of the blood vessels of the cheeks is wider than elsewhere, the vessels are nearer to the surface, and there is less tissue thickness obscuring them. This may explain why flushing occurs in that limited distribution.3 Polycythemia produces the characteristic ruddy complexion, but it may also cause a peculiar coloration termed "erythremia," which is a combination of redness and cyanosis. The tongue, lips, nose, earlobes, conjunctivae, and fingertips especially demonstrate this coloration. Erythremia results when there is a combination of increased amounts of saturated hemoglobin and desaturated hemoglobin. In some carcinoid tumors, fibrosis of the right side of the heart may lead to a combination of stenosis and regurgitation at the tricuspid valve as well as pulmonary stenosis. If cyanosis occurs, the combination of flushing and cyanosis may produce the reddish cyanotic erythremia.2 |
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Physiological Flushing: Embarrassment or anger may cause flushing in some individuals in whom the threshold for this response may be low or the reaction itself unusually intense; this is also known as blushing.1,2 Explanation and reassurance are usually sufficient. If necessary, propranolol or nadolol may be used to alleviate the symptom.1 Heat causes flushing in many patients, and overheating can lower the threshold to flushing due to other causes such as menopause.3 Overheating such as after exercise or sauna can cause physiological flushing due to the effect of the rise in blood temperature on the thermoregulatory center in the anterior hypothalamus. A similar mechanism is responsible for facial flushing due to hot drinks, which cause a rise in temperature of blood in the oral cavity in turn leading to a rise in temperature of blood perfusing the hypothalamus. The temperature of hot coffee rather than its caffeine causes flushing. A useful maneuver for patients faced with a brief thermal exposure is to suck on ice chips carried in an insulated cup. This will attenuate flushing for the first 20 to 30 minutes.3 Menopausal Flushing: About 80% of postmenopausal women experience flushing associated with sweating. A similar syndrome may also occur in men with prostate cancer receiving treatment with gonadotropin-releasing hormone analogs such as buserelin. About 65% of post-menopausal women have hot flushes for 1 to 5 years, 26% for 6 to 10 years, and 10% for more than 11 years. There is considerable variation in the frequency, intensity, and duration of hot flushes within and among individuals. A typical hot flush begins with a sensation of warmth in the head and face, followed by facial flushing that may radiate down the neck and to other parts of the body; it is associated with an increase in temperature and pulse rate and followed by a decline in temperature and profuse perspiration over the area of flush distribution. Visible changes occur in about 50% of women. Each hot flush lasts for 1 to 5 minutes. The primary role of estrogen deficiency has been questioned and a deficit of thermoregulation has been proposed. Rapid estrogen withdrawal rather than a low estrogen level by itself is likely to induce hot flushes.4 Synchronous with the onset of each hot flush is the release of a pulse of luteinizing hormone; this does not seem responsible for the hot flush since flushing can occur after hypophysectomy. The anterior hypothalamus has estrogen and progesterone receptors, and both hormones can be used effectively to treat hot flushes through binding with their respective hypothalamic receptors. Neurotransmitters that may be involved in the pathogenesis of hot flushes include norepinephrine and other noradrenergic substances. The central noradrenergic system in the hypothalamus triggers the hot flushes via α2-adrenergic receptors on the noradrenergic neurons. Thus, clonidine—an α2-adrenergic agonist—effectively alleviates hot flushes through reduction of noradrenergic release.4 Pharmacologic menopause with flushing can be induced by a variety of drugs: 4-hydroxyandrostenedione, danazol, tamoxifen, clomiphene citrate and leuprolide. Certain characteristics suggest the diagnosis of climacteric flushing: drenching perspiration, a prodromal sensation of overheating before the onset of flushing and sweating, and waking episodes at night with the typical symptoms. Alcohol can enhance a menopausal flush.5 Veralipride, an antidopaminergic drug, can cause a reduction in the frequency and intensity of menopausal flushing in premenopausal women pretreated with goserelin (gonadotropin-releasing hormone agonist) for endometriosis.6 Flushing Caused by Drugs: Other medications that can cause flushing are corticotropin-releasing hormone, doxorubicin, and niacin (Table 2). Flushing is a side effect of sildenafil citrate in 12% of patients.7 Systemic administration of morphine can cause flushing of the face, neck, and upper thorax, which is thought to be histamine-mediated.5 Patients can develop facial flushing and/or generalized erythema after epidural or intra-articular administration of glucocorticoids. The exact pathophysiology is unclear but it could be related to distention of the joint capsule.8
Flushing Associated with Alcohol Intake: Certain oriental genotypes show extensive flushing in response to low doses of alcohol. They have been found to have higher plasma levels of acetaldehyde. This abnormality is probably related to a deficiency of an isoenzyme of liver aldehyde dehydrogenase. This population can be detected by using an ethanol patch test which produces localized erythema. A special type of alcohol flush is also associated with chlorpropamide, the oral anti-hyperglycemic agent. Even small amounts of alcohol provoke intense flushing within a few minutes of ingestion. This flushing is not associated with sweating, but in some cases tachycardia, tachypnea, and hypotension may be seen. The flush is mediated by elevated acetaldehyde plasma levels and possibly by release of prostaglandins. Alcohol ingestion can trigger flushing in carcinoid tumors, mastocytosis, medullary thyroid carcinoma, and certain lymphoid tumors. Trichloroethylene, a chemical that has been abandoned in recent years because of carcinogenic potential, can cause flushing. When inhaled following ingestion of alcoholic beverages, a striking cutaneous reaction results, consisting in the sudden appearance of erythema of the face, neck, and shoulders—a reaction that has been termed "degreaser's flush." Nausea and vomiting may also occur.5 Flushing Associated with Food: Eating spicy or sour foods can cause facial flushing. This gustatory flushing is due to a neural reflex involving autonomic neurons carried by the branches of the trigeminal nerve. The flushing may be unilateral. The flushing of monosodium glutamate (MSG) is controversial. Oral challenge with MSG failed to provoke flushing in volunteers with a history of MSG flushing. Patients should be encouraged to look beyond MSG at other dietary agents, such as red pepper, other spices, nitrites and sulfites (additives in many foods), thermally hot foods and beverages, and alcohol.5 Scromboid fish poisoning (tuna and mackerel) is due to the ingestion of fish that was left in a warm temperature for hours. In addition to flushing, patients with scromboid fish poisoning have sweating, vomiting, and diarrhea. These symptoms are due to intoxication with histamine, which is thought to be generated by histidine decarboxylation by bacteria in spoiled fish. 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 Diagnosis 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 75% 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
Management 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 Etiology Histopathology Biochemical
Markers Clinical
Presentation Treatment 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 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 Auriculotemporal
Nerve 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 from 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
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 from 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 Other Diseases Causing Episodic Flushing: Cheung et al20 have described a family with monoamine oxidase deficiency causing episodes of flushing affecting the face and chest precipitated by emotion or certain foods, followed by diarrhea, headaches, and sometimes palpitations. Blood serotonin levels in this family were elevated secondary to decreased activity of monoamine oxidase. Sertraline hydrochloride controlled the symptoms by depleting platelet serotonin. Flushing is rare in patients with pheochromocytoma. If flushing occurs at all, it is seen after a paroxysm of hypertension, tachycardia, palpitations, chest pain, severe throbbing headaches, and excessive perspiration. Pallor is typically present during the attack, and mild flushing may occur after the attack as a rebound vasodilation of the facial cutaneous blood vessels.5 Facial flushing and headache can happen along with sweating of the face, neck, and upper trunk in patients with spinal cord lesions above T-6. This may occur as an exaggerated response to bowel or bladder distention.1 Other causes are certain pancreatic tumors, insulinoma, and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal proteinemia, and skin changes). Transient flushing of the face, chest, or arms has been noted after neurological deterioration secondary to rapid rise in intracranial pressure.21 |
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Persistent flushing from whatever cause may eventually lead to rosacea. The lesions of rosacea that initially occur in the central convex areas of the face consist of papules and pustules against a background of erythema, telangiectasia, edema, and eventual permanent induration or thickening of affected skin.2 Patients with severe flushing due to mastocytosis can develop rosacea in less than a year after the onset of flushing episodes.5 |
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It is important to
consider the clinical characteristics of the flushing before embarking
on expensive laboratory evaluation.5 The
physician should consider four clinical characteristics in the initial
evaluation of a patient with flushing: 1) provocative and palliative factors,
2) morphology, 3) associated features, and 4) temporal characteristics.2 |
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