Flushing
DEFINITION
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. It is the transient nature of the attacks that distinguishes flushing from the persistent erythema of photosensitivity or acute contact reactions. Repeated flushing over a prolonged period can lead to telangiectasia and occasionally to classic rosacea of the face.1
PATHOPHYSIOLOGY
Redness of the skin may be caused by 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 caused by increased blood flow through the skin, causing warmth and, because of engorgement of the subpapillary venous plexus, redness. The vasodilation of flushing may be caused by a direct action of a circulatory vasodilator substance—for example, histamine—or it may be caused by changes in the neurologic control of the cutaneous vasculature in the affected areas. In the face, neck, and upper trunk, where flushing is most frequent, the neurologic 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. Because autonomic nerve fibers also supply eccrine sweat glands, neurally activated flushing is frequently associated with sweating (wet flushing) as opposed to flushing caused by 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 physiologic 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 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
FLUSHING SYNDROMES
Physiologic 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 from other causes, such as menopause.3 Overheating, such as after exercise or sauna, can cause physiologic flushing because of the effect of the rise in blood temperature on the thermoregulatory center in the anterior hypothalamus. A similar mechanism is responsible for facial flushing caused by hot drinks, which produce a rise in temperature of blood in the oral cavity, in turn leading to an increase 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 attenuates flushing for the first 20 to 30 minutes.3
Menopausal Flushing
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 to be responsible for the hot flush, because 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 various drugs 4-hydroxyandrostenedione, danazol, tamoxifen, clomiphene citrate, and leuprolide. Certain characteristics suggest the diagnosis of climacteric flushing, such as 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 reductions in the frequency and intensity of menopausal flushing in premenopausal women pretreated with goserelin (a gonadotropin-releasing hormone agonist) for endometriosis.6
Flushing Caused by Drugs
Other medications that can cause flushing are corticotropin-releasing hormone, doxorubicin, and niacin (Box 1). 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 shoulders, which is believed to be histamine-mediated.5 Patients can develop facial flushing, generalized erythema, or both after epidural or intra-articular administration of glucocorticoids. The exact pathophysiology is unclear but could be related to distention of the joint capsule.8
Flushing Associated with Alcohol Intake
Trichloroethylene, a chemical that has been abandoned in recent years because of its 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 can also occur.5
Flushing Associated with Food
The flushing of monosodium glutamate (MSG) is controversial. Oral challenge with MSG has 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 Scombroid fish poisoning (tuna and mackerel) is caused by the ingestion of fish that was left in a warm temperature for hours. In addition to flushing, patients with scombroid fish poisoning experience sweating, vomiting, and diarrhea. These symptoms are caused by intoxication with histamine, which is believed 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 derived from a primitive stem cell that may differentiate into any of various adult endocrine-secreting cells, producing 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 (e.g., spices, chocolate, cheese, avocados, plums, walnuts,1 red sausage, red wine). With time, the flushing may appear without provocation.9 The character of the flush differs, depending on the site of origin of the tumor (Figs. 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, which may persist and lead to telangiectasia and even facial rosacea. With extensive disease, pellagra-like skin lesions can also be seen; these result from excessive uptake 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 (Fig. 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
Figure 3 Pathway for transformation of tryptophan to 5-hydroxytryptamine, niacin, and protein.
(Adapted from Greaves MW: Mastocytoses. In Champion RH, Burton JL, Burns T, Breathnach S [eds]: Rook/Wilkinson/Ebling Textbook of Dermatology, 6th ed, vol 3. Oxford, England, Blackwell Scientific, 1998, pp 2337-2346.)
Ninety-five percent of all carcinoids are found in the appendix, rectum, or small intestine.9 The remainder arise outside of the intestinal tract (e.g., in the ovary or 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 manifest with the carcinoid syndrome. Forty percent 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, hence causing flushing.9 Pulmonary or ovarian carcinoids release pharmacologic 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 caused by the 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 IV 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 carcinoids (Table 1).9
Table 1 Classification of Carcinoid Tumors According to Site of Primary Tumor
| Site | Biochemistry | Clinical Picture |
|---|---|---|
| Foregut bronchi, stomach, first part duodenum | 5-Hydroxytryptophan, adrenocorticotropin, growth hormone, gastrin, growth hormone releasing hormone | Protracted, purplish or violaceous flush, manifestation of other ectopic hormone secretion |
| Midgut second part of duodenum, jejunum, ileum, ascending colon | Serotonin, kinins, neuropeptides, prostaglandins | Pink-red flush |
| Hindgut transverse, descending colon and rectum | None | Only local symptoms |
Adapted from Vinik AI: Neuroendocrine tumors of carcinoid variety. In DeGroot LJ (ed): Endocrinology, 3rd ed, vol 3. Philadelphia, WB Saunders, 1995, pp 2803-2812.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
