Flushing? Don't sweat it!
At the 2006 Conference of the Mastocytosis Society (TMS) in Portland, Maine, in response to a question about flushing, Dr. Joseph Butterfield (pictured on left) asked whether or not a particular person sweated while flushing. Reference [Akin C, Butterfield JH, Carter MC, Castells M, Escribano L, Verstovsek S. Panel Discussion. Portland, Maine: The Mastocytosis Society, 2006]. Then he commented, “Well, flushers that sweat…the flushing tends to be cholinergic nerve discharge, which is not typical of mediator-induced flushing, which is more typical of mast cell disease. There are two different kinds of flushes — the sweaters and the non-sweaters.”
That response got a laugh from the audience, but the distinction is one that has puzzled some of us. Why does it matter whether or not you sweat when you flush? Why is that so important in trying to distinguish between mast cell-related flushing and other causes of flushing?
In this article, I’m going to try to answer those questions, and while we’re at it, I’ll share some of the fun facts I’ve dug up on the subjects of sweating and flushing.
For instance, did you know that as we age, the number of sweat glands that we have decreases? This effect is most easily observed in our feet. One study [Ferrer T, Ramos MJ, Perez-Sales P, Perez-Jimenez A, Alvares E. Sympathetic sudomotor function and aging. Muscle Nerve. 1995; 18:7] found that below age 30, healthy participants had 213 sweat glands per square centimeter in their feet. Between age 30 and 59, the number went down to 199, and over age 59, the average was 123 sweat glands per square centimeter. That means that between age 29 and 60, we may lose over 40 percent of the sweat glands in our feet!
Also, younger people have higher output of sweat per sweat gland. So, it’s not surprising that older people find it harder to regulate their bodily temperature — they’ve got fewer and less efficient sweat glands to work with.
Fun facts about sweating
The medical terms (Piper T, ed. Stedman's Electronic Medical Dictionary, version 7.0. (Mac version 10.2.) Wolters Kluwer Health / Lippincott Williams & Wilkins; 2007) for sweating include diaphoresis and sudation.
People who have diabetes often have problems sweating in their extremities (that is, in their arms and legs, including hands and feet), and as a result the sweat glands in their torsos overcompensate. Reference [Ertl AC, Pfeifer M, Davis SN. Diabetic Autonomic Dysfunction. In: Robertson D, editor. Primer on the Autonomic Nervous System. 2nd ed. Boston: Elsevier; 2004; 328–31]. However, as the diabetes worsens, the person can become completely anhidrotic, which means that he or she cannot sweat at all. If this happens, it puts the person at a greatly increased risk of heat stroke.
Men have a lower threshold for when they begin sweating, and their sweat glands have a higher output than do women’s. Reference [Fealey RD. Disorders of Sweating. In: Robertson D, editor. Primer on the Autonomic Nervous System. 2nd ed. Boston: Elsevier; 2004; 353–8]. But the threshold temperature at which anyone begins to sweat varies throughout the day — it is highest between midnight and 4:00 AM.
Also, our sweating can adjust itself as conditions change — for example, as we do endurance training or are exposed to chronic heat or humidity, our sweating output increases.
Well, enough about sweating. How about flushing?
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The term “flush” was first coined in 1882 by Dr. E.J. Tilt, who was searching for a short, expressive way to refer to this phenomenon. Reference [Izikson L, English JC, III, Zirwas MJ. The flushing patient: Differential diagnosis, workup, and treatment. J Am Acad Dermatol. 2006; 55:193–208].
Dr. Christain Nasr [Nasr C. Flushing. In: Carey WD, Hoogwerf B, eds. The Disease Management Project. Cleveland: The Cleveland Clinic; 2004] defines flushing as: “…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 [redness] of photosensitivity or acute contact reactions. Repeated flushing over a prolonged period of time can lead to telangiectasia [dilation of previously existing small or terminal blood vessels] and occasionally to classical rosacea of the face.”
Telangiectasia and rosacea are familiar terms to many of us with mast cell-related diseases. However, just to refresh your memory, telangiectasia is the term used to describe dilation of previously existing small or terminal blood vessels, while rosacea describes chronic dilation of blood vessels in the nose and connected areas of the cheek. Reference [Piper T, ed. Stedman's Electronic Medical Dictionary, version 7.0. (Mac version 10.2.) Wolters Kluwer Health / Lippincott Williams & Wilkins; 2007].
The physical mechanism underlying flushing involves “an increased amount of saturated hemoglobin, an increase in the diameter or actual number of skin capillaries, or a combination of these factors.” Reference [Nasr C. Flushing. In: Carey WD, Hoogwerf B, eds. The Disease Management Project. Cleveland: The Cleveland Clinic; 2004]. The most common causes of flushing are fever, hyperthermia (heat-related illnesses such as heatstroke or sunstroke), emotional blushing, menopause, and rosacea. Reference [Izikson L, English JC, III, Zirwas MJ. The flushing patient: Differential diagnosis, workup, and treatment. J Am Acad Dermatol. 2006; 55:193–208].
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What causes flushing
There are many different substances that can cause flushing, and which ones are at work is related to the specific cause of the flushing. In Table 1, the specific mediators of flushing due to various causes are listed. It should be noted that according to Izikson et al. [Izikson L, English JC, III, Zirwas MJ. The flushing patient: Differential diagnosis, workup, and treatment. J Am Acad Dermatol. 2006; 55:193–208], “With the exception of carcinoids, flushing due to tumors is rare and tends to occur in advanced stages.”
Table 1. The mediators of flushing
|Foods, beverages, alcohol||Tyramine (present in ergot, mistletoe, ripe cheese, beer, red wine, and putrefied animal matter), histamine, sulfites, nitrites, alcohol, aldehyde, higher chain alcohols, monosodium glutamate (MSG), capsaicin (which is what makes chili peppers hot), and cigua toxin (fish)|
|Mastocytosis, anaphylaxis, and mast cell-related disorders||Histamine, prostaglandin D2, leukotrienes, tumor necrosis factor α (alpha), vascular endothelial growth factor, interleukins, heparin, and acid hydrolases|
|Carcinoid syndrome (symptoms and lesions produced by the release of serotonin from carcinoid tumors of the GI tract that have metastasized to the liver)||5-hydroxytryptamine (5-HT; no flushing but diarrhea), substance P, histamine, catecholamines, prostaglandins, kallikrein, kinins, tachykinins, neurotensin, neuropeptide K, vasoactive intestinal polypeptide (VIP), gastrin-related peptide, and motilin|
|Pheochromocytoma (a usually benign neoplasm in the adrenal gland’s medullary tissue)||Catecholamines (epinephrine, norepinephrine, dopamine), vasoactive intestinal polypeptide (VIP), calcitonin-gene-related peptide, and adrenomedullin|
|Medullary carcinoma of the thyroid||Calcitonin, prostaglandins, histamine, substance P, levodopa, ketacalcin, adrenocorticotropic hormone, and corticotropin-releasing hormone|
|Pancreatic cell carcinoma||Vasoactive intestinal polypeptide (VIP), prostaglandin, and gastric inhibitory polypeptide|
|Renal cell carcinoma||Prostaglandins and pituitary down-regulation|
|Neurologic||Substance P and catecholamines|
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Flushing vs. flushing and sweating
While there is some overlap between the mediators produced by the various conditions that cause flushing, it’s not hard to see how a physician could pin down the cause of flushing if he or she were able to figure out what specific mediators were involved.
And while there are very benign causes of flushing, such as changes in temperature, emotional state, or exertion, as well as eating spicy food, flushing can also be a symptom of a serious physical condition.
But what about that “cholinergic nerve discharge” that Dr. Butterfield mentioned? What is that, and how can we tell the difference between that and mast cell-mediated flushing?
The sympathetic nervous system’s neurons release acetylcholine (a neurotransmitter, or substance that transmits messages within the nervous system), which causes both sweat gland activity and dilation of blood vessels. Reference [Boron WF, Boulpaep EL. Medical Physiology: A Cellular and Molecular Approach. Updated ed. Philadelphia: Elsevier Saunders; 2005]. So, when you see someone both sweating and “turning red,” you are probably witnessing flushing that is due the cholinergic effects of the sympathetic nervous system.
In contrast, when histamine is released by mast cells in the skin, it has the effect of dilating blood vessels, but the histamine does not have an effect on the sweat glands. Reference [Simons FER. Histamine and H1-Antihistamines in Allergic Disease. Second, revised and expanded ed. New York: Marcel Dekker, Inc.; 2002].
So when we see flushing without sweating, it’s more likely to be caused by histamine release in the skin, whereas when we see flushing and sweating together, it’s more likely to be caused by the release of acetylcholine by the sympathetic nervous system.
There’s only one caveat to this explanation: When a person is going into shock, they will often begin sweating profusely, and as we know, anaphylaxis can send someone into shock. Reference [Marx JA, editor-in-chief. Rosen's Emergency Medicine: Concepts and Clinical Practice. 6th, online ed. Philadelphia: Mosby Elsevier; 2006]. So, sweating in the later stages of a mast cell crisis is to be expected — it’s only in the early stages that we expect flushing without sweating. ◊
An earlier version of this article appeared in the Fall 2007 issue of The Mastocytosis Chronicles, the quarterly newsletter of the Mastocytosis Society (TMS).
Page last updated: March 20, 2011