Disorders of Flushing STEVEN H. YALE,1,5 SHIKHA VASUDEVA,1 JOSEPH J. MAZZA,2,5 LOREN ROLAK,3,5 JODI ARROWOOD,6 SARA STICHERT,6 AND ERIK S. 4,5 STRATMAN 1 Department of Internal Medicine; 2Department of Hematology and Oncology; 3Department of Neurology; 4Department of Dermatology; 5 Marshfield Clinic, Marshfield Clinic Research Foundation; and 6Pharmacy, St Joseph’s Hospital, Marshfield, WI 54449 ORIGINAL ARTICLE Disorders of flushing encompass a broad spectrum of diverse acquired and inherited conditions. Chemical mediators involved in the flushing response are incompletely understood. Flushing episodes rarely can be associated with significant morbidity and mortality. The goal of the physician is to separate benign from potentially life-threatening conditions. Accurate diagnosis requires a thorough history and physical examination emphasizing the age of the patient, temporal association of flushing with occupation, environmental, stress, food, or drug exposure, and the duration of the episode. In some cases, despite a thorough evaluation, the etiology for flushing remains unknown. Understanding the distinct mechanisms that lead to flushing helps provide a rational approach to treatment. INTRODUCTION REPRINTS Steven H. Yale, MD, Clinical Research Center, Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, WI 54449. E-mail: yale.steven@mcrf.mfldclin.edu The authors have stated that they do not have a significant financial interest or other relationship with any product manufacturer or provider of services discussed in this article. The authors also do not discuss the use of off-label products, which includes unlabeled, unapproved, or investigative products or devices. Submitted for publication: October 20, 2004. Accepted: October 25, 2004. Comprehensive Therapy, vol. 31, no. 1, Spring 2005 © Copyright 2005 by ASCMS All rights of any nature whatsoever reserved. 0098-8243/05/31:59–71/$30.00 Flushing is the term used to describe a warm, transient redness of the skin caused by increased cutaneous blood flow because of capillary dilatation. Flushing disorders are distinguished on the basis of their frequency, duration, and temporal association with endogenous or exogenous exposures such as drug and other organic compounds (Table 1). A variety of chemical mediators including endogenous enkephalins, endorphins, prostaglandins, and histamine are known to induce flushing (1–4). Recognizing the role that these chemical mediators and other neurotransmitters play in the pathogenesis of flushing provides a rational basis for management of clinical symptoms. PAT H O P H Y S I O L O G Y Flushing has a predilection for the face, neck, and upper chest where the upper dermis is the thinnest, capacitance is greatest, and less tissue fluid is obstructing the superficial cutaneous vasculature (5). Neural, immunological, and direct neurohumoral mechanisms are involved in the pathogenesis of flushing. Neural-induced flushing (wet flush) is distinguished from immunological and direct humoral causes (dry flush) by the presence of sympathetic cholinergic neuronal activation of ecrine sweat glands (6,7). COMP THER. 2005;31(1).......................................................................59 TA B L E 1 Causes of Flushinga Allergic (immune/nonimmune) Acute hemolytic reaction Anaphylactoid reaction Cold urticaria Drug hypersensitivity syndromes Graft-vs-host disease Hereditary vibratory angioedema Hypereosinophilic syndrome Immediate hypersensitivity syndromes Latex Cardiovascular Aortic insufficiency Mitral stenosis Orthostatic hypotension Vertebrobasilar insufficiency Congenital Congenital gustatory with facial flushing Congenital Horner’s syndrome Rosving’s syndrome Frey’s syndrome Dermatological Rosacea Mast-cell diseases (urticaria pigmentosa, TMEP, mastocytoma) Endocrine Dumping syndrome Hyperendorphin syndrome Hyperthyroidism Hypoglycemia Hypophysectomy Food Caffeine withdrawal syndrome Hot beverages Spicy foods Kava Monosodium glutamate Nitrites Sulfite Hormone suppression Menopause Orchiectomy Pituitary adenoma Inherited Alcohol intolerance Monoamine oxidase deficiency Injection Epidural steroid injection Intra-articular steroid injection Malignancy (see Table 5) Medications (see Table 4) Miscellaneous Hyperthermia Neurological Aberrant parasympathetic innervation Autonomic hyperreflexia Cluster headache Colloid cyst of the third ventricle Diabetic autonomic neuropathy Diencephalic autonomic epilepsy Harlequin syndrome Migraine Multiple sclerosis Parkinson’s disease Porfour du petit syndrome Post-herpetic cutaneous scarring Postural orthostatic hypotension Posttraumatic syringomyelia Ross’s syndrome Serotonin syndrome Trigeminal neuralgia Organic solvents Carbon disulfide Cyanamide Dimethylformamide Thiuram derivatives Trichloroethylene N-butyraldoxine Xylene Physiological Reactive erythemas Psychiatric Panic disorder Catatonia Organic psychosis Stress Surgical Auricuolotemporal (Frey’s) syndrome Harlequin syndrome Mesenteric traction Toxin Scorpion bite Scromboid poisoning a References available on request. TMEP, telangiectasia macularis eruptiva perstans. Sympathetic vasodilator and vasoconstrictor sudomotor fibers normally control sweating and blood flow to the face (8). Activation of the sympathetic cholinergic neurons leads to dilatation of the superficial capillary network of the skin, causing increased blood flow, elevated skin temperature, and diaphoresis and inhibition of sympathetic nerves through stellate ganglion block prevents facial flushing (9). Other postulated mechanisms involved in the facial vasodilatation response include (a) antidromic release of substance P or serotonin from the trigeminal nerve, and (b) activation of the greater superficial petrosal nerve, sphenopalatine and otic ganglions releasing vasoactive intestinal peptide (8,10). Flushing from exogenous factors such as consumption of a hot beverage is a normal physiological response resulting from a countercurrent mechanism for heat exchange between the internal carotid and internal jugular vein. The hypothalamus responds to this increased temperature by activating heat dissipation mechanisms leading to vasodilation and flushing (10). A variety of neurohormones including histamine, prostaglandins, endorphins, substance P, bradykinin, serotonin, and catecholamines are potential causes of flushing. In the flushing response, catecholamines work through indirect mechanisms by releasing kallikren and bradykinin, which results in cutaneous vasodilatation (11). Flushing secondary to rosacea, menopause, and other flushing disorders may be caused by endogenous enkephalins and/or opioids because opioid antagonists abolish flushing (12–17). PHYSIOLOGICAL Flushing or blushing is not uncommonly seen during socially embarrassing or stressful situations and occurs as an exaggerated autonomic response. Physiological flushing may occur as a thermoregulatory response for the dissipation of heat after strenuous activity (exerciseinduced thermal flushing), ambient changes in temperature, febrile illness, or consumption of a hot beverage. Repeated and prolonged exposure may result in facial erythema and permanent facial telangiectasias. ROSACEA Rosacea is a common, chronic, cyclic inflammatory, heterogeneous clinical syndrome of unknown etiology (18). Patients may present with a variety of symptoms including flushing, burning, stinging, papules, pustules, erythema, telangiectasias, and phymatous changes of the nose, chin, cheeks, and glabella. During the early stages, it is characterized by blushing followed by periods of facial redness, telangiectasia, and inflammation (19). With repetitive cycles, flushing becomes more permanent and facial redness deepens. The persistent erythema and telangiectasia may be caused by repeated episodes of facial flushing. The disease is most commonly confined to the nose, cheeks, chin, or forehead (18,20). Women between the ages of 30 and 50 are most commonly affected (19). More than 90% of patients with rosacea experience flushing with episodes occurring daily in more than 60% of those affected (18,21). Flushing is believed to be under vasomotor control and is generally the initial clinical symptom to appear with each episode lasting up to 30 min (21,22). Flushing may be provoked by a number of environmental factors including hot spicy foods and alcohol. β-Blockers (B1 selective and nonselective), oral and topical antibiotics, and antihistamines have been used in the treatment of erythema and flushing seen in rosacea (19,21). ALCOHOL-INDUCED FLUSHING Flushing caused by alcohol consumption is the result of both acquired and inherited factors (Tables 2 and 3). Flushing typically occurs within 20–30 min after ingestion with symptoms resolving within 3–4 h. A variety of mediators have been implicated in this process, including acetaldehyde, catecholamines, histamine, opioids, and prostaglandins (12,23). Inherited causes of flushing related to alcohol consumption are due to genetic polymorphisms at the alcohol/aldehyde dehydrogenase enzyme and are more commonly seen in women, Asians, and Native Americans (24,134). Regardless of the genetic variant, acetaldehyde accumulates and is believed to be an important contributor to the flushing reaction associated with alcohol consumption (25,26). Alcohol is metabolized in the liver primarily by class I alcohol dehydrogenase (ADH) to acetaldehyde and by aldehyde dehydrogenase (ALDH2) to acetate. About 50% of Asians also show genetic polymorphisms for mitochondrial ALDH2 and thus have an impaired rate of metabolism of acetaldehyde in the liver (24). These differences in the rate of acetaldehyde production or catabolism may account for varied individual responses to alcohol-induced flushing (27,28). However, the relationship between the propensity, intensity, and genetic polymorphism to flush is not clearly established (29). Other proponents including catecholamines, histamine, opioids, and prostaglandins are involved in the flushing response to alcohol ingestion (2,29). Sympathomimetic and vasomotor properties of alcohol and acetaldehyde result in increased levels of catecholamines (epinephrine/norepinephrine), opioids, prostaglandins, and kinnins, along with the release of histamine from COMP THER. 2005;31(1) ..............................................................61 TA B L E 2 Drugs Causing Flushing Due to Alcohol Sensitizationa Calcium carbamide Cephalosporins (cefoperazone, cefamandol, moxalactam, cefotetan) chloramphenicol Chloral hydrate Chlorpropamide Clotrimazole Disulfuram Griseofluvin Metronidazole Monoamine oxidase inhibitors Phentolamine Procarbazine Quinacrine aReferences available on request. TA B L E 3 and important mediators in alcohol-induced flushing (3). Furthermore, prostaglandin inhibitors are known to suppress the flushing response seen in individuals with genetically determined isoenzyme deficiencies. Histamine antagonists (H1 and H2), nonsteroidal anti-inflammatory medications, and opioid antagonists diminish the intensity of the alcohol-induced flush reaction without affecting alcohol absorption or acetaldehyde levels (23,25,32,33). H1 and H2 antagonists indirectly reduce flushing by decreasing gastric motility and by lowering the rate at which alcohol is absorbed (34). The clinical manifestations of alcohol-induced flushing are similar to those experienced by individuals taking drugs such as disulfiram and chlorpropramide and consuming alcohol. Symptoms include facial flushing, headache, tachycardia, sweating, nausea, increased skin temperature, and decreased blood pressure (35,36). These drugs inhibit the enzyme acetaldehyde dehydrogenase, thereby causing increased acetaldehyde levels. Disulfiram additionally inhibits dopamine B hydroxylase, an enzyme responsible for the formation of norpinephrine (a vasoconstrictor). Thus, the combined effects of elevated aldehyde and decreased norepinephrine levels leads to vasodilation (37). Acquired Causes of Alcohol-Induced Flushinga SUPPRESSED HORMONE PRODUCTION Carbon disulfide exposure Carcinoid tumors Corinus mushroom injestion Dimethylformamide Hypereosonophilic syndromes Lymphomas Myeloproliferative diseases Medullary thyroid carcinoma Mastocytosis Menopause Polycythemia rubra vera Rosacea Trichlorethylene Manipulation of estrogen and testosterone production, either naturally or through chemical or surgical intervention, can result in vasomotor symptoms. Thus, vasomotor flushing is commonly seen in postmenopausal women, premenopausal women after oophorectomy, and men after bilateral surgical orchiectomy or hormone suppression therapy used in the treatment of prostate cancer. This is thought to result from the abrupt change in hormonal and gonadotropin levels caused by these events (38–40). Within 3 mo of surgical or natural menopause, 60% of women complain of vasomotor flushing (38). In the perimenopausal period, the hot flash, described as an intense feeling of warmth usually lasting from 30 s to 5 min and occurring frequently throughout the day, often precedes the appearance of the vasomotor flush. The flush is either a blush or a patchy rash that typically starts in the chest and neck and ascends to cover the entire face and may be provoked by alcohol, warm temperatures, hot drinks, or emotional stress. The flush can be associated with other local or systemic symptoms, including perspiration, tachycardia, and increased respiratory rate. Postmenopausal flushing typically lasts 1–2 yr but may continue for many years. aReferences available on request. mast cells (3,12,30). Tyramine or histamine found in fermented alcoholic beverages including beer, sherry, or wine have been implicated to cause flushing and headaches (31). Acetaldehyde is a potent stimulator of prostaglandin (prostacyclin) production, which are arterial vasodilators COMP THER. 2005;31(1) ..............................................................62 The etiology for vasomotor hot flashes seen in menopause is incompletely understood and appears to be in part, the result of an altered sympathetic control of peripheral blood flow. Several theories explaining the pathogenesis of vasomotor flushing have been developed. Various mediators, in addition to estrogen and progesterone, may play a role in causing hot flashes. These include endorphins, catecholamines, catecholestrogens, prostaglandins, and luteinizing hormone (LH) (39). Although declining estrogen levels and elevated gonadotropin levels are a necessary prerequisite for the development of vasomotor symptoms, they do not explain the pathophysiology of menopausal flushing (41). The hot flashes are known to occur independently of surges in LH because patients may still experience symptoms after hypophysectomy (42). It is postulated that declining estrogen or testosterone levels result from decreased endogenous opioid activity in the hypothalamus. Opioids in the hypothalamus and brain stem normally inhibit noradrenergic activity and modulate the release of calcitonin-gene related peptides (CGRP) from the thermoregulatory centers of the hypothalamus (43). Decreased opioid levels lead to a series of events including central sympathetic activation, catecholamine and CGRP release from the hypothalamus, gonadotropin-releasing hormone (GnRH) secretion, and activation of the thermoregulatory centers of the medial pre-optic region of the hypothalamus (38,39,44,45). This is the site mediating heat loss pathways (46), resulting in both vasodilation and increased cholinergic sweating (43). Estrogens are useful in the short-term treatment of hot flashes. Their long-term use may be associated with severe adverse consequences such as venothromboembolism and increased risk of breast cancer (47). Megesterol acetate has also been useful in the management of hot flashes secondary to androgen deprivation for prostate cancer and in postmenopausal women with contraindications to estrogen use (48,49). Clonidine, venlafaxine, paroxetine, and gabapentin have demonstrated efficacy in the treatment of hot flashes in men and in individuals whom estrogens are contraindicated (50). O C C U PAT I O N A L Occupational exposure to the organic solvent dimethylformamide (DMF) causes flushing both spontaneously and after ethanol ingestion (51). The mechanism is postulated to be because of inhibition of alcohol dehydrogenase enzyme by the DMF metabolite N-methylformamide, which subsequently increases acetaldehyde levels. Both n-butyral-doxine and thiuran derivatives used in the printing and rubber industry has been associated with flushing reaction (52) (Table 1). DRUGS The mechanism of drug-induced flushing differs according to the drug class, dose, metabolism, and route of administration (Table 4). Drug-induced flushing typically is self-limiting, occurs spontaneously, disappears on discontinuation of the medication, and in some cases occurs after alcohol ingestion. In the case of ethanolinduced flushing, various drugs “sensitize” the individual to flushing (Table 2). Flushing may also be caused by immunological (antibody-induced) or nonimmunological mechanisms. Drugs such as vancomycin and morphine cause flushing through nonimmunological direct histamine release. Drug-related flushing is frequently rapid, occurring within minutes after administration of the medication. However, in the case of GnRH antagonists, the onset typically occurs about 2–7 wk after administration. This is because of downregulation of pituitary GnRH receptors and a subsequent decrease in estrogen levels (53). Transient flushing occurs on exposure to radiocontrast media, consumption of foods containing nitrites, or inhalation of amyl nitrate. Flushing as a result of vancomycin, dihydropyridine calcium channel blockers, niacin, or immunoglobulins may be decreased or abolished by reducing the dose, decreasing the infusion rate, and discontinuing the medication if necessary (54–58). In the case of niacin, flushing is prostaglandin-mediated and may be prevented or reduced by administering prostaglandin inhibitors (e.g., aspirin) 30 min prior to ingestion or by reducing the dose (59). Patients can often develop tolerance to the flushing with repeated doses. Interestingly, drugs that have been used in the treatment of flushing secondary to menopause, rosacea, nicotinic acid, and paroxysmal diencephalic epilepsy, can paradoxically cause or worsen flushing on abrupt withdrawal (60). Patients with diabetes mellitus who are treated with chlorpropramide and tolbutamide can develop flush after alcohol consumption (61–63). Unlike the response observed in certain ethnic groups in response to alcohol ingestion, there is no known genetic basis for this reaction (64–66). The presence of higher levels of acetaldehyde in these patients suggests that chlorpropramide acts as a noncompetitive inhibitor of aldehyde dehydrogenase (67–70). However, prostaglandins and endogenous enkephalins with opioid-like activities such as mentenkephalins are also reported to be involved in the COMP THER. 2005;31(1) ..............................................................63 TA B L E 4 Drugs Associated With Flushinga Antibiotics Cephalosporins (cefoperazone, cefamandol, moxalactam, cefotetan) Chloramphenicol Griseofulvin Metronidazole Quinacrine Trimethoprim/sulfamethaxazole Trimetraxate Vancomycin Antidepressants Monoamine oxidase inhibitors Serotonin syndrome Tricyclic antidepressant toxicity Antihyperglycemic Chlorpropamide Tolbutamide Antihypertensives Angiotensin-converting enzyme inhibitors Calcium channel blockers (amlodipine, felodipine, nifedipine, nicardipine, isradipine) Diazoxide Hydralazine Phentolamine Reserpine Histamine-releasing drugs Intravenous contrast agents Neuromuscular blocking agents (i.e., tubocurarine) Opiates Aspirin Alcohol Hormones Bromocriptine Calcitonin Corticotropin releasing hormone Desmopressin LHRH agonist (lueprororelin) Thyroid-releasing hormone Immunosuppressants/cytokines/chemotherapeutic agents Corticosteroids (dexamethosone/ methylprednisolone) Cyclosporin intravenous Cytabarine COMP THER. 2005;31(1) ..............................................................64 Dacarbazine Doxorubicin 5-Fluorouracil Glitiramer Granulocyte colony-stimulating factor Granulocyte/macrophage colony-stimulating factor Hydroxyurea (Hydrea) Infliximab Interleukin II, III Interferon-α2 Lymphocyte immune globulin Melphalan (alkeran) Plicamycin (mithramicin) Procarbazine Tamoxifen Trimetraxate Others Amiodarone IV Amyl nitrate Chloral hydrate Cholinergic agents Disulfuram Ergotamine Fenfluramine R-Hirudin Iron dextran Isoflurane-fentanyl Metachlorpropamide Niacin Nicotine Nitroglycerin Omeprazole Phenelzine Sildenafil Theophylline Peptides Atrial natruretic factor Adenosine Calcitonin aReferences available on request. LHRH, luteinizing hormone-releasing hormone. flushing response to chlorpropramide (16,70–73). The propensity to develop flushing is dependent on the dose of medication, blood concentration, duration of action, and individual’s body weight (70,74,75). FOOD Increased nitrous oxide (NO) production causes vasodilatation and flushing (76). Ingested glutamate, which activates the NO neurotransmission pathway, may be responsible for both the “Hot Dog Headache” and the “Chinese Restaurant Syndrome” (77). Red pepper and capsaicin found within spicy foods (78) and preservatives such as nitrites, sodium benzoate, and sulfites added to cured meats, hot dogs, bacon, and ham has also been associated with flushing (79). Rapid onset of wheezing, flushing, and hypotension may be because of sulfite found in beer, cider, wine, frozen vegetables, and fruit juices (31). H Y P E R A D R E N E R G I C S TAT E S This group of disorders is characterized by autonomic and hyperadrenergic manifestations that include flushing, chest pain, lightheadedness, diaphoresis, palpitations, nausea, and headaches. Drugs are frequently responsible for these symptoms, as are panic disorder and paroxysmal hypertension (pseudopheochromocytoma) (80). In addition to classic adrenergic symptoms, patients with panic attacks typically report spontaneous onset of apprehension and a feeling of impending doom. Cutaneous flushing, in addition to paroxysms of hypertension and headache, has been described in a patient with a loss of vagal afferent input, because of radiation damage to both the carotid and aortic baroreceptors (81). These receptors are important in the normal control of heart rate and inhibition of efferent sympathetic activity in response to changes in blood pressure and are a manifestation of spontaneous fluctuation in sympathetic tone not regulated by an intact arterial baroreceptor reflex. ENDOCRINE AND NEUROENDOCRINE Neuroendocrine tumors are a diverse group of diseases that are believed to originate from stem cells of neuroendocrine origin and differentiate into multiple cell lines capable of endocrine activity (Table 5). Recent classification emphasizes the role of the cells of origin, histological variability, and hormone production (82). Carcinoid Tumors Flushing, cardiac valve disease, and diarrhea constitute the classic triad of carcinoid syndrome, but the full constellation of symptoms occurs in less than 10% of patients (83,84). The carcinoid syndrome is typically seen in the setting where there is direct venous access to TA B L E 5 Tumors Associated With Flushinga Basophilic chronic granulocytic leukemia Carcinoid Carotid body tumor Castleman’s disease Ganglioneuroblastoma Gastrinoma Gastro-pancreatic tumors Glioblastoma multiforme of the pre-optic area Glomus jugulare tumor Glucagonoma Islet cell tumor Malignant histocytoma Mast-cell disease (mast-cell leukemia, mastocytoma , systemic mastocytosis) Medullary carcinoma of thyroid Neurotensinomas Osteosclerotic myeloma (POEMS) Ovarian teratoma Pancreatic tumors producing vasoactive intestinal peptides Pancreatic polypeptide (pp)-PPOMA Paraganglionomas Pheochromocytoma Pituitary tumor (nonfunctioning) Renal-cell tumors Small-cell carcinomas Somatostatinoma Vasoactive intestinal peptides a References available on request. the systemic circulation (85). Thus, carcinoid tumors of the gastrointestinal tract do not characteristically produce this syndrome in the absence of hepatic metastases (86). Anatomical site, endocrine secretion or metastatic potential are important factors that determine whether carcinoid tumors produce carcinoid syndrome (87). Clinical signs and symptoms reflect the predominant hormone secreted by the tumor (88). Potential mediators responsible for flushing include histamine, tachykinins, prostaglandins, dopamine, neurotensin, and substance P (4,82,89). Although serotonin and its metabolites are elevated in carcinoid syndrome, they do not seem to cause flushing because flushing can occur independently of or persist despite reduction in serotonin COMP THER. 2005;31(1) ..............................................................65 and 5-hydroxyindolacetic acid (5HIAA) levels. Furthermore, flushing does not correlate with elevation in serotonin or bradykinin levels (90). Small bowel carcinoid, metastatic tumors to the liver, primary carcinoid tumors in the lung, ovaries or stomach, and noncarcinoid tumors such as small-cell carcinoma of the lung and islet cell carcinoma of the pancreas can all cause flushing (86), which may be the primary and only symptom (85). The characteristics of the flushing symptoms can provide clues regarding the origin of these tumors because they reflect the different chemical mediators released from these tumors (91). Flushing from the small bowel carcinoid tumors involves the face, neck, and upper trunk extending to the nipple line. The flush tends to occur frequently throughout the day and lasts only several minutes (7,78). Early in the course of the disease, the flushing typically is provoked or aggravated by hot foods, foods containing tyramine or alcohol, exercise, and periods of emotional stress. Eventually, the flushing occurs spontaneously and unlike flushing from lung or bronchial carcinoids, no residual redness remains from these episodes. Bronchial carcinoids produce a purplish flush compared to the typical vivid red and white patchy geographic flush involving the head and neck seen in gastric carcinoids (87,91). Furthermore, in bronchial carcinoids, the episodes of flushing are more intense and diffuse, last hours, and are associated with lacrimation and conjunctival suffusion. Recurrent episodes may lead to permanent skin thickening and telangiectasias (85,91). Lung and bronchial carcinoids may be associated with ectopic hormone production and flushing in the presence of low to normal 5HIAA levels (92). Thus, assay for 5-hydroxytryptophan (5HTP) may be necessary in patients with normal 5HIAA levels who have a clinical syndrome suggesting carcinoid. Measurements of the neuropeptides, tachykinins, neuropeptide K, neurokinin A, and substance P (93,94) may be useful in establishing the diagnosis, evaluating for early recurrence, or following the course of the disease in cases where 5HIAA and serum 5HT values are normal (85). Mastocytosis Mastocytosis is the term used to describe a group of cutaneous or systemic disorders caused by increased numbers of benign or neoplastic proliferation of mast cells (96,97). The most common presenting signs and symptoms are skin lesions reflecting mast-cell infiltration and degranulation or mediator release. Patients typically present with periodic episodes of spontaneous or triggered symptoms of cutaneous flushing and hypotension (96,98). Systemic mastocytosis and carcinoid tumors share many of the same clinical features including flushing, hepatomegaly, and diarrhea. However, in contrast to the transient flush seen in various types of carcinoid, flushing because of mastocytosis typically lasts 20 min or longer (99). Prostaglandins and histamine are believed to be responsible for both flush and hypotension (99). Signs and symptoms reflect increased mast-cell burden or histamine release and include organomegaly, urticaria pigmentosa, gastroesophageal reflux, asthma, and diarrhea. Diagnosis is suggested by symptoms in the presence of elevated urinary histamine, 1-methyl-4-imidazoleactic acid, N-methylhistamine, PGD2, PGF2, or serum tryptase levels particularly after a flushing episode and confirmed by biopsy of involved tissue (96,100,101). There is currently no cure for mastocytosis and treatment is largely supportive with interventions directed at blocking mediator release from mast cells or blocking the effects of mast-cell mediators on various organ systems. Treatment modalities available include cromolyn sodium, anticholinergics, antihistamines (H1 and H2), and in some patients high-dose aspirin (53,102). Pheochromocytoma Pheochromocytoma is a rare tumor arising from chromaffin cells of the sympathoadrenal axis. Flushing is uncommonly seen in patients with pheochromocytoma and generally lasts for 10–45 min. The presence of this symptom suggests that the tumor is producing epinephrine, dopamine, or a concomitant mediator such as vasoactive intestinal peptide or substance P (7,103). Medullary Carcinoma of the Thyroid Pseudocarcinoid Syndrome The term pseudocarcinoid syndrome describes a clinical condition in men characterized by elevated urinary 5HIAA levels, secondary hypogonadism, and flushing. The cause for the increased levels of 5HIAA is unknown but may be related to or mediated by tachykinin and neuropeptide K. This disorder should be considered in men whose clinical symptoms suggest carcinoid syndrome (95). COMP THER. 2005;31(1) ..............................................................66 Medullary carcinoma of the thyroid is a rare neuroendocrine tumor arising from the parafollicular cells of the thyroid gland. The flush can produce permanent skin changes similar to that seen in bronchial and lung carcinoid tumors. Medullary carcinoma of the thyroid should be suspected when flushing is seen in the presence of pheochromocytoma, parathyroid hyperplasia, mucosal neuromas, and other manifestations of multiple endocrine neoplasia (MEN II) syndrome. Calcitonin is the primary hormone secreted by these tumors and is believed to be one of the mediators responsible for flushing and diarrhea. Additionally, prostaglandins, histamine, L-dopa and substance P have been suggested to be involved in the flushing reaction (104). Prostaglandin inhibitors are known to inhibit the flush induced by pentagastrin stimulation. The diagnosis of tumor-associated flushing disorders can be suggested by biochemical blood and urine abnormalities and confirmed by histopathological evaluation of a tissue specimen. Plasma-free metanephrine and serum tryptase levels or 24-h urine collection for 5HIAA and histamine after the flushing episode may provide clues to an underlying pheochromocytoma, systemic mastocytosis, or carcinoid tumor, respectively (7,105–107). Other sophisticated laboratory measurements may be required if the diagnosis is suspected but the initial screening tests are inconclusive. Pancreastatin and chromogranins A and B are produced by neuroendocrine tumors and are markers for neuroendocrine differentiation (108). Elevations in these nonspecific biochemical markers are useful when symptoms suggest a neuroendocrine tumor but initial screening studies are nondiagnostic. Computed tomography (CT) and magnetic resonance imaging (MRI) should only be performed after a thorough history and physical examination and initial screening tests reveal abnormal results. Diagnosis of an endocrine tumor may require ultrasound, CT, MRI, nuclear imaging, and positron emission tomography (PET) scanning. Scintiography and PET scanning are particularly important to clarify nondiagnostic CT and MRI scanning, or to determine whether distant metastases are present (82,106,108,109). If localized, primary tumors are resected for curative intent. Unfortunately, most neuroendocrine tumors are metastatic at the time of diagnosis. Somatostatin analogs have been useful adjuvants in reducing neuroendocrine secretion in some patients with medullary thyroid carcinomas, vasoactive intestinal peptide and carcinoid tumors (109–111). T O X I N - M E D I AT E D Scromboid poisoning is a clinical syndrome caused by the ingestion of a preformed heat stable toxin that accumulates when fish is not properly refrigerated. Histamine is the presumed toxin that is formed under warm conditions by the decarboxylation of histidine by the enzyme histidine decarboxylase elaborated or produced by bacteria such as proteus species, Escherichia coli, Salmonella species, and Klebsiella sp on the surface of the fish (112,113). Other vasoactive amines, such as putrescine and cadaverine, inhibit enzymes that are responsible for detoxifying histamine, thereby increasing histamine levels (114). The stability of the toxin on heating prevents its degradation during cooking or commercial processing (115). Histamine in the gastrointestinal tract is converted to N-acetylhistamine, which is rapidly absorbed. Although the poisoning was first noted in patients who consumed fish of the scromboid family (e.g., tuna, mackarel) it has since been described in other nonscromboid species such as mahi mahi, bluefish, herring, sardines, Australian salmon, and anchovies (112,113). Signs and symptoms occur within 30 min after ingestion of the affected fish and include skin erythema and urticaria, flushing, palpitations, headache, nausea, vomiting, and dizziness (112,113). Management of scromboid fish toxin ingestion includes both histamine 1 and histamine 2 blockers, and for moderate to severe symptoms, gastric lavage and activated charcoal. In severe cases, an anaphylactic reaction may occur, which requires aggressive systemic intervention with epinephrine and/or corticosteroids (113). AUTONOMIC SYNDROMES Neurological conditions are rare causes of flushing. Congenital disorders of flushing can occur as sporadic or inherited abnormalities of the autonomic system. Abnormal cross-innervation of the skin and sweat glands by parasympathetic nerves normally supplied by postganglionic sympathetic nerves at birth, or after parotidectomy or suppurative parotiditis, defines congenital gustatory unilateral flushing and auriculotemporal (Frey’s) syndrome, respectively (116,117). In response to gustatory and occasionally tactile stimuli, patients develop symptoms of flushing and sweating localized to the face in a distribution that includes the region anterior to the tragus, midpoint of the cheek and temporal region (117). In both of these disorders, parasympathetic nerves of the auriculotemporal and cervical plexus join postganglionic sympathetic fibers that normally supply the sweat glands of the skin and cutaneous vessels (118). The result is facial flushing and sweating with mastication in the previously supplied sympathetic facial skin region. A surgical block has been employed in preventing the underlying symptoms in patients with Frey’s syndrome. A cross-innervation syndrome analogous to Frey’s syndrome has been described in a patient with trigeminal herpes zoster with post-herpetic scarring (119). Harlequin syndrome is an acquired flushing response because of ablation of the contralateral first- or COMP THER. 2005;31(1) ..............................................................67 second-order sympathetic neurons at the levels of the second or third thoracic segment of the spinal cord or superior cervical ganglion, resulting from congenital, surgical, or tumor involvement (6,120–122). The Harlequin sign is a term used to describe unilateral facial flushing seen in conjunction with Horner’s syndrome (upper lid ptosis), pupil miosis, and anhidrosis. Facial flushing and sweating are seen on the side of the face opposite to that of the lesion. The affected side will demonstrate decreased skin temperature because of impairment of sympathetic vasodilation (8,123). Facial flushing may result from release of tonic sympathetic vasoconstriction, active sympathetic vasodilation, increased parasympathetic activity through the greater petrosal nerve and the release of vasoactive peptides. Idiopathic hemifacial hyperhidrosis occurs after bilateral cervicothoracic sympathectomy with reinnervation of the superior cervical sympathetic ganglion by preganglionic sympathetic fibers destined for sweat glands. Diencephalic epilepsy is a clinical syndrome caused by paroxysmal autonomic epileptic discharge from the mesial temporal lobe. The diagnosis should be considered in patients presenting with syncopal spells and aural symptoms preceding autonomic symptoms of hypertension, tachycardia, and flushing (124). Autonomic dysreflexia occurs in persons who have sustained a spinal cord injury above the sixth thoracic vertebra. A stimulus below this level leads to uncontrolled reflex sympathetic activity resulting in hypertensive episodes and flushing. These symptoms can be avoided if early warning signs such as flushing, sweating, and increased spasticity are recognized and excessive stimulation is minimized (125). Poufour du Petit syndrome consists of a dilated pupil and flushing occurring as a result of sympathetic over-activity owing to injury of the sympathetic plexus surrounding the carotid artery (135). HYPERSENSITIVITY Anaphylaxis is an immediate hypersensitivity reaction that occurs in susceptible individuals on exposure to an exogenous allergen, or in the absence of an identifiable precipitating factor. Clinical manifestations that are useful in differentiating anaphylaxis from other causes of flushing include urticaria, pruritus, angioedema, and hypotension. The etiology of the immediate generalized reaction can be IgE-mediated. The mechanism is unknown in cases where there is no apparent external source (126). Hereditary vibratory angioedema and cold-induced urticaria are rare causes for flushing (52). Latex allergy COMP THER. 2005;31(1) ..............................................................68 has been recognized as an important occult cause of flushing especially among health care workers (127,128). I D I O PAT H I C F L U S H I N G Idiopathic flushing is used to describe a clinical condition characterized by recurrent episodes of cutaneous flushing and constitutional symptoms in the absence of any known disorder (129). Idiopathic flushing has a higher predilection for young women, who typically have a longer duration of symptoms (130). In addition to flushing, symptoms of palpitations, hypotension, and diarrhea have been reported. H I S T O RY A N D P H Y S I C A L E X A M I N AT I O N A thorough and accurate history and careful examination is the first and most critical step in the evaluation of a patient and should focus on the clinical course, duration of symptoms, provoking and relieving symptoms, as well as the presence and absence of other symptoms including sweating. Initial assessment should distinguish flushing from other conditions that cause a red face (131). A red face is a localized process superimposed on an underlying disorder affecting the skin (e.g., atopic dermatitis, erysipelas, or seborrheic dermatitis). The redness is typically present throughout the day with variable periods of fluctuating intensity. Flushing, in contrast, is a transient erythema occurring in the absence of another disorder of the skin. Flushing may be caused by the presence of an underlying disease as well as drug or toxin exposure. The history should focus on determining whether there is a temporal association with exposure to drugs, alcohol, foods, or chemicals and duration of symptoms (Table 1). Flushing lasting hours tends to be because of endogenous release of chemical mediators such as histamine as seen in the variety of neuroendocrine tumors and drugs. A history of flushing after alcohol ingestion can be useful in narrowing the differential diagnosis (Tables 2 and 3). A previous history of atopy or multiple allergies should prompt consideration of an allergic reaction to drugs, latex, or anaphylaxis as the cause for flushing. In women, inquiries regarding menstrual cycle history and the presence of vasomotor symptoms can confirm menopause as the cause for symptoms. Determining whether other people have experienced similar symptoms suggests a common food source or occupational exposure. The presence of flushing with other symptoms including diarrhea, headache, sweating, and asthma requires evaluation for a neuroendocrine tumor. Patients with carcinoid and mastocytosis may present with stigmata including facial flushing, connective tissue hypertrophy, and ocular findings indistinguishable from rosacea (18). Physical examination should include evaluating the thyroid for enlargement or mass. Axillary freckling and caufe au lait spots are suggestive of pheochromocytoma. The presence of a wheel and flare after stroking a red-brown macular rash is pathognomonic for mastocytosis. An endocrine tumor should be suspected when palpation of a mass produces symptoms of flushing, hypotension, hypertension, and confusion. T R E AT M E N T Because hot flashes are induced by thermogenic stimuli, avoidance of conditions such as warm temperatures and hot drinks may be helpful in reducing the frequency of flushing (132). Certain medications, such as clonidine have been used in the treatment of recalcitrant rosacea, postorchiectomy, and postmenopausal flush (21,133). Clonidine’s mechanism of action includes stimulation of central α-2 presynaptic receptors, thus secondarily reducing noradrenergic transmission. Clonidine may also act directly on the peripheral vasculature thereby inhibiting vasodilation. This suggests that different etiologies utilize common pathways in the pathophysiologic mechanism of flushing. Treatment is directed toward the cause, which in most cases involves removing the offending agent or providing symptomatic relief. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. CONCLUSION Determining a specific etiology for flushing symptoms may be a diagnostic challenge. A thorough evaluation including an accurate history is often helpful in determining the underlying cause. 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