Dermatology

Flushing

Are You Confident of the Diagnosis?

What you should be alert for in the history

The following questions are helpful in narrowing down the differential diagnosis of the flushing patient:

- Is the flushing intermittent or persistent?

- If the flushing is intermittent, how long do the episodes of flushing last?

- How often do flushing episodes occur?

- What is the distribution of the redness and/or sensation of warmth?

- Is the flushing associated with concomitant strong emotion?

- Is the flushing associated with concurrent sweating (distinguishing “wet flushing” from “dry flushing”) or diarrhea?

- Are there any associated triggers?

- Are there any eye symptoms?

- What medications has the patient taken?

- Are the episodes of flushing associated with any of the following: fever; diaphoresis; fatigue; malaise; weight loss; eye redness or dryness; rhinorrhea; swelling of the tongue, mouth, or lips; wheezing (asthma); difficulty breathing; chest pain; palpitations; tachycardia; lightheadedness/syncope; abdominal cramping or pain; nausea; vomiting; diarrhea; hematuria; flank pain; perimenopausal/menopausal/postmenopausal timing; headache; skin dryness; or urticaria?

Characteristic findings on physical examination

On physical exam, there may or may not be specific physical findings, especially if the patient is not currently having an episode of flushing; however, one should look for certain clues that can help narrow down the differential diagnosis.

Intermittent or persistent erythema, limited to the face, with papules, pustules, telangiectasias, or rhinophymatous changes suggests a diagnosis of rosacea. An examination of the eyes for associated signs of ocular rosacea is helpful for diagnosis; most commonly, patients have blepharitis and conjunctivitis.

In a perimenopausal patient, climacteric flushing typically involves the head, neck, and chest, and is associated with severe sweating and warmth. The so-called “hot flashes” typically last approximately 3-5 minutes, and women may experience numerous episodes throughout a day.

The flushing associated with carcinoid syndrome has been described as reddish-brown or bright-red flushing, and it can be generalized. Erythema of the palms can be seen with this syndrome. Patients may have permanent telangiectasia, and they may have a bluish tint to the skin on their face.

In the setting of mastocytosis, there may be a number of clues on physical exam, including red-brown macules or papules. If there are cutaneous lesions, one can check for a positive Darier’s sign to help aid in this diagnosis. Darier’s sign is the urtication of a cutaneous lesion following the cautious stroking of one of the lesions with the back of a cotton-tipped applicator or tongue depressor.

The presence of dermatographism, hives, or localized edema suggests a diagnosis of urticaria, angioedema, or anaphylaxis. Persistent flushing of the face and arms with possible associated telangiectasias and skin discoloration, especially if a thyroid nodule is appreciated on exam, suggests a diagnosis of medullary carcinoma of the thyroid.

Expected results of diagnostic studies

Expected results of diagnostic studies, as well as the differential diagnosis of flushing can be found in the tables below.

Who is at Risk for Developing this Disease?

The epidemiology and risk factors for flushing depend on the underlying etiology.

What is the Cause of the Disease?

Etiology

Flushing is caused by increased cutaneous blood flow, with resultant increased redness, and often warmth, in the skin. It is a common chief complaint among patients, and its underlying causes are many. Indeed, the differential diagnosis of flushing is long and encompasses both common and rare entities, as well as both benign and malignant disorders.

Pathophysiology

The most common causes of flushing are the following conditions: benign cutaneous flushing (caused by food or beverages, hyperthermia, exercise, or emotions), fever, climacteric flushing (i.e. menopausal “hot flashes” due to decreased estrogen levels), rosacea, alcohol, and certain medications.

The medications that most commonly produce a flushing response are vasodilators (including calcium channel blockers), phosphodiesterase 5 inhibitors, nitroglycerin, and nicotinic acid.

Niacin, or nicotinic acid, is a B-complex vitamin (vitamin B3), and is effective for the treatment of dyslipidemia. Patients commonly complain of flushing, and most will experience mild to moderate symptoms, which decrease over time with continued use of the medication. An estimated 5%-20% of patients experience severe flushing episodes, limiting their ability to adhere to the treatment regimen.

Flushing due to niacin results from an increase in circulating prostaglandin D2, which then binds to receptors on capillaries leading to vasodilation. Concomitant use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) can counteract the rise in prostaglandin D2 through cyclooxygenase blockade of prostaglandin D2 synthesis, and thus blunt niacin’s flushing side effect.

Other ways to minimize intense flushing episodes are as follows: taking the niacin with a low-fat meal, avoiding simultaneous ingestion of alcohol or hot beverages, and starting the niacin at a low dose, with slow titration to the full dose, as tolerated. It has been suggested that good counseling of patients prior to starting therapy will help them manage the flushing better and ensure improved compliance.

Alcohol may lead to flushing through its metabolite acetaldehyde, which is a potent vasodilator. Patients with an alcohol dehydrogenase deficiency (common in Asian populations) quickly experience flushing with alcohol ingestion as acetaldehyde builds up, signaling to the adrenal medulla and sympathetic nerves to release catecholamines, which in turn leads to vasodilation.

Medications that systemically inhibit the enzyme alcohol dehydrogenase will cause a flushing response when combined with alcohol.

Topical calcineurin inhibitors (pimecrolimus and tacrolimus) have led to localized facial flushing when combined with alcohol consumption. In general, the flushing occurs 5-10 minutes following alcohol ingestion, and the reaction begins 2-4 weeks after initiation of treatment with the topical medications, which are often used to treat atopic dermatitis, seborrheic dermatitis, vitiligo, or other inflammatory conditions of the face.

There are a number of hypotheses about why this may occur. Currently, neither the predictive factors nor the incidence of this phenomenon, is known. It is worth noting that topical calcineurin inhibitors have also been reported to cause a rosacea-like dermatitis, independent of alcohol use, beginning 2-3 weeks after initiating therapy.

Flushing may be due to vasodilation caused by the response of vascular smooth muscle to either autonomic innervation or circulating vasodilating mediators. Because of autonomic innervation of eccrine glands, flushing caused by an autonomic stimulus is combined with sweating, or so-called “wet flushing.”

Vasodilation in response to circulating vasodilating mediators may result in flushing without sweating, or so-called “dry flushing.” Circulating vasodilating mediators may be exogenous, such as from ingested substances, or endogenous mediators, such as those associated with a systemic disorder.

Systemic Implications and Complications

The rarer, but malignant or life-threatening, causes of flushing include anaphylaxis, carcinoid syndrome (CS), mastocytosis, medullary carcinoma of the thyroid, pancreatic cell tumor (e.g. Vasoactive Intestinal Polypeptide tumor

[VIPoma]), renal cell carcinoma (RCC), and pheochromocytoma.

Flushing due to anaphylaxis is a true medical emergency. It is due to mast cell and basophil release of vasoactive substances. The flushing of anaphylaxis is often accompanied by other signs and symptoms: urticaria; angioedema; wheezing or swelling of the tongue, lips, or oropharynx; shortness of breath; nausea or abdominal pain; and hypotension.

Flushing due to anaphylaxis is generally diagnosed on a clinical basis; however, confirmatory lab tests include elevated serum levels of histamine and tryptase during episodes. Acutely, the patient must be stabilized, and administration of epinephrine, as well as antihistamines, may be life-saving. Supportive care and careful monitoring is also appropriate.

Identification and avoidance of triggers is essential for patients who suffer from anaphylaxis. Once the patient is stabilized, consultation to an allergy specialist for further evaluation and management may be warranted. Many patients who suffer from an anaphylactic episode carry around a personal dose of epinephrine (Epipen), in case they experience a repeat episode.

Flushing due to CS is a rare but important diagnosis to rule out, owing to its potential for mortality. CS occurs in approximately 10% of patients with a carcinoid tumor, which is a malignancy of neuroendocrine-derived enterochromaffin or Kulchitsky cells. The occurence of CS depends on the types of mediators secreted by the tumor cells, as well as the presence and amount of liver metastases. Tumors located distal to the portal system are more likely to cause CS.

The classic triad of CS is flushing, gastrointestinal symptoms (abdominal cramping, abdominal pain, and diarrhea), and right-sided cardiac failure. Most do not present with this triad; however, upwards of 90% of patients with CS experience flushing.

The flushing associated with CS is said to be distinctive. Patients with a gastric carcinoid tumor often flush with a reddish-brown color and variegated appearance. The flushing may be generalized, and the palms and soles may be involved as well. There may be severe pruritus during the episodes of flushing.

Patients who experience bronchoconstriction as part of their condition often develop confluent, generalized, bright-red flushing, which may last for hours or persist for days. These episodes may be associated with other signs, including facial edema, oliguria, and hypotension. Over years, if the flushing episodes continue, patients may develop a bluish coloration to the central face, as well as telangiectasias and skin thickening. Flushing episodes may be triggered by various medications, foods, or physical or emotional stimuli that provoke an adrenergic response.

Diagnosing flushing due to mastocytosis may require a high index of suspicion, especially when the presentation is not that of urticaria pigmentosa. Mastocytosis should be considered when the flushing is seen in combination with hypotension. The extent of cutaneous involvement and the morphology of skin lesions vary, especially in the adult population.

Adults have a higher incidence of systemic symptoms, complete blood cell abnormalities, and c-kit activating mutations, conferring protracted disease and systemic involvement. In the pediatric population, mastocytosis is most commonly manifested as urticaria pigmentosa. The characteristic reddish-brown macules, papules, plaques, or nodules exhibit a positive Darier sign.

In all forms of mastocytosis, flushing episodes may flare in the setting of certain medications, as well as physical and emotional stimuli. See Mastocytosis for further characterization of clinical presentations, workup, and treatments.

Persistent flushing caused by medullary carcinoma of the thyroid may involve the face or upper extremities, and it may be accompanied by telangiectasias. In this setting, the flushing is caused by vasoactive peptides secreted by the tumor. This type of thyroid carcinoma may be seen as part of multiple endocrine neoplasia syndrome, due to a RET gene mutation. An asymptomatic thyroid nodule may be palpated on exam.

The workup may include serum calcitonin levels, radioimmunoassay for calcitonin following intravenous calcium and pentagastrin administration, thyroid nuclear scanning, and fine-needle aspiration of the mass. If this diagnosis is suspected, consult endocrinology and surgery. One should also consider other possible associations, such as pheochromocytoma and hyperparathyroidism.

Flushing caused by pancreatic cell tumors, such as a VIPoma, often will present with other concomitant symptoms, such as watery diarrhea, dehydration, low potassium, and achlorhydria. The patients may be lethargic and exhibit weakness, muscle cramping, nausea, vomiting, or abdominal pain. Some patients may exhibit hyperglycemia, but this is a minority.

Flushing, when present, generally occurs during attacks secondary to tumor secretion of physiologically active peptides. An elevated VIP level in the setting of watery diarrhea will confirm the diagnosis. A serum chromogranin A level may also be elevated in patients with a VIPoma. Imaging studies should be performed to localize the tumor. Surgical or medical management may be neccessary, depending on the location and extent of disease on imaging.

Flushing due to RCC is caused by secretion of vasoactive substances. The classic triad associated with RCC consists of an abdominal mass, flank pain, and gross hematuria. However, the minority of patients with RCC (fewer than 10%) present with this triad. The majority of patients present with hematuria or systemic symptoms such as anorexia, wasting, and fatigue.

Lab tests may reveal anemia, eosinophilia, or leukocytosis. A high index of suspicion and imaging studies are required to diagnose this condition in the flushing patient. Once a tumor is identified, the patient should be referred to surgery for evaluation of radical nephrectomy. Other medical therapies, such as chemotherapy, may be warranted in some cases.

Pheochromocytoma is a rare catecholamine-secreting tumor of chromaffin cells in the adrenal medulla (approximately 80-85% of cases), or more rarely, the paraganglia (extra-adrenal pheochromocytomas are referred to as “paragangliomas”). They are most commonly sporadic, or they may be associated with a genetic disorder, notably multiple endocrine neoplasia syndrome type 2A and 2B, neurofibromatosis type 1, von Hippel-Lindau Disease, familial extra-adrenal paraganglioma, and pheochromocytoma syndrome.

Pheochromocytoma classically presents in patients with paroxysmal episodes of headaches, palpitations, shortness of breath, sweating, and flushing, in conjunction with hypertension. However, approximately 60% of patients with pheochromocytoma have labile but sustained hypertension, while approximately 4% of patients demonstrate hypertension during crises. Patients may also have gastrointestinal symptoms, as well as chest pain and a feeling of impending doom.

The direct effects of catecholamines and other secreted mediators on vascular smooth muscle, as well as increased blood pressure and cardiac output, leads to flushing in these patients. Diagnosis is based on measurement of 24-hour urine fractionated metanephrines. Further imaging studies may be indicated to precisely localize the tumor.

A (123)I-metaiodobenzylguanidine scintigraphy should be performed if catecholamine levels are not elevated but a pheochromocytoma is suspected. Unopposed beta-blockade should be avoided in such patients, and beta blockers are reserved for treatment only after treatment with alpha blockers has been initiated. Definitive treatment is by surgical excision of the pheochromocytoma, which may be curative.

Several genetic disorders confer an increased risk for pheochromocytoma, though the majority are sporadic. Such genetic diseases are neurofibromatosis type 1, multiple endocrine neoplasia type 2A, von Hippel-Lindau disease, familial extra-adrenal paragangliomas, and pheochromocytomas syndrome. One should have a suspicion of possible pheochromocytoma in young patients who present with hypertension, or who have signs or symptoms of the aforementioned genetic diseases.

Other causes of Flushing are listed in Table I(substances in food).

Table I.

Other causes of Flushing
flushing caused by autonomic stimulus (flushing + sweating or “wet flushing”) Diagnostic clues Diagnostic work-up Treatment
Thermoregulatory flushingFever, exercise, hyperthermia Elevated body temperature, increased ambient temperature, recent exercise, recent ingestion of hot beverage None - Antipyretics for fever- Cooling blankets- Adjustment in ambient temperature- Allowance of time for hot beverages to cool- Ingestion of a cold beverage
Emotional flushing or blushing Episodes triggered by emotional triggers, common in patients of Celtic descent; affects women more commonly than men None - cover-up makeup with a green tint- beta blockers, such as nadolol
Climacteric flushingMenopausal “hot flashes” Peri- or menopausal woman, episodic episodes of flushing and intense sweating lasting 3-4 minutes occurring up to twenty times per day.Episodes may be distressing and may interfere with sleep or activities of daily living. Serum FSH (elevated) - Alpha-2 agonist (e.g. clonidine via transdermal patch delivery at 0.1mg/day or orally at doses between 0.1 and 0.4mg three times daily.)- Estrogen replacement therapy or progestin administration in conjunction with patient’s gynecologist may be helpful in reducing symptoms- SSRIs (e.g. extended release venlafaxine at 75mg daily) However, not all SSRIs have shown benefits compared to placebo in trials.  SSRIs must be used with caution in women with a history of breast cancer who are undergoing tamoxifen therapy.-Gabapentin may reduce the frequency of hot flashes.  Doses of 300mg to 600mg at bedtime may be useful.
Neurologic flushingMigraine, cluster headache, Parkinson’s disease, multiple sclerosis, trigeminal neuralgia, CNS tumor, Horner syndrome, Frey syndrome/auriculotemporal syndrome/gustatory flushing, autonomic epilepsy, autonomic hyperreflexia/spinal cord injury, orthostatic hypotension, Streeten syndrome/postural orthostatic tachycardia syndrome History of neurologic disorder, spinal cord injury, trigeminal nerve injury (including post-herpetic neuralgia, history of parotid surgery or birth/childhood facial trauma)   Referral to neurologist
Psychiatric disordersAnxiety, panic disorder, depression, somatization disorder History of these disorders   Referral to psychiatrist
(Flushing without sweating or “dry flushing”)      
Rosacea Facial flushing, especially in response to known triggers, facial burning, telangiectasias, papules or pustules, ocular symptoms. Over time, persistent facial flushing and edema may occur, as well as rhinophymatous changes in some patients. NoneSkin biopsy (rarely performed, as the diagnosis is usually made by history and physical exam) - In general, the flushing component of rosacea is difficult to treat- Avoidance of triggers- Avoidance of sun- Topical or systemic antibiotics (e.g. metronidazole 1% daily, azelaic acid 20% twice daily, sodium sulfacetamide lotion, clindamycin 1% or benzoyl peroxide)  - Green-tinted cover-up- Topical retinoids (e.g. tretinoin)- Oral antibiotics (e.g. tetracyclines)- Laser therapy (especially helpful for associated telangiectasia)- Botulinum toxin-A has been reported effective in case reports, however, due to potential side effects and lack of evidence in randomized, placebo-controlled clinical trials, this method is not generally endorsed
Food or beverage ingestion History of foods or beverages triggering episodes None -Avoidance of triggers
Medications Medication historyThe most common classes of medications causing flushing are vasodilators None - Avoidance of medication, dose or formulation change in conjunction with the prescribing physician- Effective symptomatic therapy depends on mechanism of action-inducing flushing
Alcohol History of alcohol triggering episodes, seen especially in patients of Asian descent, because of alcohol dehydrogenase 2 deficiency leading to an accumulation of acetaldehyde (a metabolite that increases circulating catecholamines via the adrenal medulla and sympathetic nerves)Alcohol may also trigger episodes of flushing when combined with certain medications  None -Avoidance-Moderation-Aspirin and antihistamines may decrease the flushing response when taken with alcohol
Anaphylaxis Flushing associated with urticaria, tongue or lip swelling, stridor, hypotension, abdominal pain - Serum tryptase level (elevated only during episode)- Consider referral to an allergist  - Recognition of emergency and potentially life-threatening condition- Strict avoidance of known triggers- Subcutaneous epinephrine- Antihistamines
Carcinoid syndrome Flushes from gastric carcinoid tumors tend to have a red-brown coloration and be associated with urticarial lesions, whereas bronchial carcinoid tumors tend to lead to bright red, confluent flushing.  Flushing episodes may be associated with hypotension, tachycardia, diarrhea, and bronchospasm, and may be triggered by stimuli such as alcohol, chocolate, and beef.   24-hour urine for  5-hydroxyindolacetic acid [5-HIAA] levels (elevated) - Somatostatin- Octreotide- Lantreotide- Antihistamines with combination H1 and H2 blockers- Ketanserin (5-HT antagonist)- Surgical resection, when possible- Chemotherapy
Systemic mastocytosis Characteristic skin lesions of urticaria pigmentosa, such as red-brown macules, papules or plaques, which exhibit a positive Darier Sign (lesion urtication following stroking). Flushing may be associated with hypotension, tachycardia, anaphylaxis, abdominal cramping, diarrhea, nausea, vomiting or fevers.  Systemic symptoms may be triggered by mast-cell degranulators.   - Serum tryptase level (persistently elevated)- 24-hour urine - n-methylhistamine and prostaglandin D2 levels (elevated)- Skin biopsy- Bone marrow biopsy in adults - Avoidance of mast cell degranulators- Symptom-based treatments for flushing include: H1-blocking antihistamines.- For concomitant pruritus, consider adding H2-blocking antihistamines, topical steroids,   photochemotherapy, or systemic steroids. (See Mastocytosis for further treatment details)- Further symptom-based treatments for systemic mastocytosis affecting other organs (See Mastocytosis)- Cytoreductive therapy, reserved for patients with end-organ damage in the setting of systemic disease (referral to oncologist)
Pheochromocytoma Headaches, sweating, tachycardia, breathlessness, hypertension, which may be sustained or episodic, a feeling of doom, nausea, vomiting, chest or abdominal pain. Episodes may last minutes-hours.  Flushing more commonly follows an episode, but can also occur during an episode because of catecholamine release and increased cardiac output. 24-hour urinary catecholamine and fractionated metanephrine levels. Patients may have history of neurofibromatosis, multiple endocrine neoplasia (MEN) Type II syndrome, von Hippel-Lindau disease, and familial extra-adrenal paragangliomas and pheochromocytoma. Also consider the diagnosis in a young patient presenting with hypertension or a family history of the above syndromes. - 24-hour urine fractionated metanephrines- platelet norepinephrine levels- 123I-metaiodobenzo-guanidine- (123I-MIBG) scintigraphy (useful in suspected cases with normal 24-hour urine and platelet screening) - Evaluation and genetic testing for associated syndromes if clinically suspected based on history and physical exam. - Alpha receptor blockers (e.g. phenoxybenzamine at initial doses of 10mg once or twice daily or phentolamine for hypertensive crises)- Surgical intervention
Medullary thyroid carcinoma Facial and upper extremity flushing. Telangiectasias may be seen on face and arms, as well.  A thyroid nodule may be picked up on exam.  May be seen as part of MEN syndrome. - Calcitonin levels (elevated)- Calcitonin radioimmune assay- Endocrine consult- Fine needle aspiration of thyroid nodule - Consider evaluation for MEN syndrome - Referral to endocrinologist- Surgical management
Pancreatic tumorVIPoma Watery diarrhea - Plasma VIP levels (elevated)  
Renal cell carcinoma Gross hematuria, palpable abdominal mass and flank pain.  (Triad only seen in ~10% of patients).  Fever, night sweats, weight loss, fatigue, and anemia may also be noted on review of systems.  Flushing may occur due to gonadotropin-like substances released from the tumor, which act to down-regulate the pituitary gland.  - Urinalysis (hematuria)- CBC (anemia)- Imaging to assess for abdominal mass  
Serotonin syndrome Medication history, with attention to possible medication interactions. Sweating, hyperthermia may be associated with flushing because of the autonomic hyperreactivity seen in this syndrome. None  
Other Rare Causes of Flushing      
Dumping syndrome History of bypass or other gastrointestinal surgery, resulting in shortened transit time. Tachycardia, sweating, hypotension, and dizziness may be associated with flushing; episodes often follow meals, hot beverage intake, or high glucose load. None  
SarcoidosisLupus pernio subtype Facial flushing due to granuloma infiltration of cutaneous blood vessels - Skin biopsy- Chest radiograph- Serum ACE level See Sarcoidosis
Hyperthyroidism Characteristic skin and hair changes Thyroid function tests Referral to an endocrinologist
Bronchogenic carcinoma      
Androgen deficiency in males Men with low testosterone, a history of prostate cancer on androgen-deprivation therapy, history of bilateral orchiectomy    
Mitral valve stenosis Chronic malar flush and cyanosis    
POEMS syndrome (a plasma cell proliferative disorder, usually multiple myeloma, associated with polyneuropathy, organomegaly, endocrinopathy or edema, M-protein, and skin abnormalities) Hyperpigmentation, hypertrichosis, glomeruloid angiomas, skin thickening   Referral to an oncologist
Basophilic granulocytic leukemia     Referral to an oncologist
Malignant histiocytoma      
Peri-aortic surgery      
Leigh syndrome (subacute necrotizing encephalomyelopathy) caused by mutations of mitochondrial DNA      
Rovsing syndromeHorseshoe kidney accompanied by nausea and abdominal discomfort Associated umbilical pain caused by vascular compression    

Exogenous substances found in food and beverages that may induce flushing, and their possible sources are summarized in Table II.

Table II.

Exogenous substances found in food and beverages that may induce flushing, and their possible sources.
Ingredients in food and beverages that cause flushing Sources of ingredients
Tyramine Aged cheeses, overripe or dried fruits (e.g. avocado, eggplant, figs, grapes, raisins, oranges, pineapples, plums, prunes, banana peels), processed foods (yeast extract, sauerkraut, shrimp paste, processed/pickled/cured/dried/canned meats including fish, bouillon cubes for making broth), fermented soy products (e.g. soy sauce, tofu, miso, teriyaki sauce), beer, Chianti wine, vermouth, fava beans, protein supplements
Histamine Fermented cheeses, beer, wine, smoked fish, anchovies, fruits and vegetables*Eating spoiled or inadequately stored/refrigerated fish such as tuna, mackerel, mahi mahi, and others results in the accumulation of histamine, which is not destroyed by cooking.  The resultant syndrome, scombroid, is caused by the ingestion of histamine, and symptoms begin within an hour of ingesting the fish. It is often confused with a hypersensitivity or allergic reaction.
Monosodium glutamate (MSG) Fermented foods, including cheeses, meats, bouillon cubes, flavoring mixes, fast food restaurants*The FDA requires labeling if foods contain MSG
 Sulfites (potassium metabisulfite)  Wine, dried fruits, preservatives*The FDA requires labeling of only wine containing sulfites, however other foods may contain sulfites as a preservative, but may not be labeled as such
 Nitrites  Cured meats and fish, vegetables
 Capsaicin  Spicy foods (active ingredient in chili peppers from the plants of genus Capsicum)
 Ciguatoxin Produced by the dinoflagellate, Gambierdiscus toxicus; accumulates in coral reef fish such as amberjack, grouper, wrasse, and triggerfish, especially in the skin, head, viscera and roe.  The toxin is not destroyed by cooking.

There are also a variety of medications known to cause flushing. These include:

Vasodilators (nitroglycerin), nitric-oxide-releasers (sildenafil, vardenafil, tadalafil)

  • Niacin (nicotinic acid, vitamin B3)

  • Nicotine

  • Calcium channel blockers

  • Dihydropyridine agents (nifedipine, nisoldipine, amlodipine) cause flushing more commonly than nondihydropyridine agents (diltiazem, verapamil)

  • Beta blockers

  • Angiotensin-converting enzyme inhibitors

  • Opiates (e.g. morphine)

  • NSAIDs

  • Contrast media

  • Prostaglandins D2, E

  • Enkephalin analogs

  • Cholinergic medications

  • Catecholamines

  • Bromocriptine

  • Chemotherapeutic agents

  • High-dose methylprednisolone and other systemic steroids, including intra-articular corticosteroid injections

  • Withdrawal of long-term use of topical steroids

  • Antiemetics (e.g. alizapride, metoclopramide)

  • Leuprolide

  • Cyproterone acetate

  • Vancomycin (red man syndrome)

  • Rifampin

  • Calcitonin gene-related peptide

  • Thyrotropin-releasing hormone

  • General anesthetics

  • Gold therapy for rheumatologic conditions

  • Caffeine withdrawal

The following medications, when combined with alcohol, can cause flushing:

Disulfiram

  • Metronidazole

  • Ketoconazole

  • Griseofulvin

  • Cephalosporins

  • Chloramphenicol

  • Antimalarials/quinacrine

  • Chlorpropamide

  • Calcium carbamide

  • Phentolamine

  • Coprinus mushroom ingestion

  • Topical tacrolimus

  • Topical pimecrolimus

  • Industrial solvents

Treatment Options

Treatment is tailored to the underlying condition. For exogenous triggers, avoidance of the triggering agent is most helpful.

For patients with medication-induced flushing, avoidance, when possible, will likewise improve the flushing; however, occasionally a change in medication formulation or dosing may result in amelioration of flushing symptoms. In the case of niacin, adding aspirin may dramatically improve symptoms. Some flushing episodes associated with medications may decrease in intensity or frequency over time.

In general, patient education and counseling is instrumental in setting patients’ expectations and helping them understand and potentially tolerate flushing.

Optimal Therapeutic Approach for this Disease

The optimal therapy for flushing varies, depending on its etiology. Optimal treatment for each type of flushing is provided in Table I.

Patient Management

Several algorithms for the diagnostic workup of the flushing patient have been suggested and published. Essentially, the history and physical exam are essential in elucidating findings that are suggestive of an underlying disorder. For patients in which the diagnosis is not immediately clear following initial history and physical exam, it has been recommended that the patients keep a diary for 2 weeks in order to help identify possible triggers associated with flushing episodes, as well as any associated symptoms.

If no obvious cause or diagnosis is suggested, it has been suggested that screening evaluation should be used to rule out common or serious causes. This may include a complete blood count; liver function tests; urinalysis; 24-hour urine for 5-hydroxyindoleacetic acid (5-HIAA), fractionated metanephrines, and prostaglandin D2 metabolites; serum serotonin; tryptase; and histamine levels. If the diagnosis remains elusive despite the above workup, idiopathic, psychiatric, or rare causes of flushing should be considered. Additionally, referral to endocrine, allergy, or psychiatric specialists may be warranted for further evaluation and treatment.

Unusual Clinical Scenarios to Consider in Patient Management

Several unusual scenarios for flushing exist and warrant further discussion:

Patients with a variety of neurologic diseases may develop flushing. Flushing in these circumstances is often a result of autonomic dysfunction and vascular dilatation. Damage to the trigeminal nerve may result in flushing with accompanied pain, burning, or numbness. Migraines may be associated with flushing.

Flushing may also occur in the following: Horner’s synrome, with flushing occurring on the unaffected side; auriculotemporal flushing, or Frey syndrome, due to abnormal regeneration of autonomic nerve fibers following birth trauma or other facial trauma; autonomic epilepsy due to sporadic release of catecholamines; and autonomic hyperreflexia due to spinal cord disorders. Orthostatic hypotension, Streeten syndrome, and Harlequin syndrome also are associated with episodes of flushing.

Patients with psychiatric disorders, such as anxiety or panic disorder, may experience episodes of flushing. These episodes are often accompanied by sweating and other symptoms such as palpitations, chest pain, shortness of breath, feelings of doom, or faintness. In patients presenting with unexplained flushing, one must rule out organic etiologies prior to suspecting a solely psychiatric origin. Once other causes have been ruled out, a referral to a psychiatrist may be very helpful in determining the underlying cause, as well as providing treatments for the psychiatric condition.

Scombroid, a type of fish poisoning caused by an accumulation of histamine within the flesh of spoiled fish, results in severe flushing, nausea, vomiting, palpitations, and pruritus. It is easily confused with an allergic reaction or anaphylaxis. Once histamine accumulates during the thawing and spoiling process, it is not inactivated through cooking methods. Antihistamines are the mainstay of treatment, and severe episodes may require supportive care or evaluation by emergency personnel. This condition may be the true etiology of some patients’ presumed seafood allergy.

Other conditions rarely associated with flushing include the following: the lupus pernio variant of sarcoid; valvular heart disease (mitral valve disorders, in particular, may result in a bluish malar flush); polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome; “dumping syndrome” following bariatric surgery; androgen deficiency in males; basophilic granulocytic leukemia; as well as some other cancers.

Rovsing syndrome, or patients with a horseshoe kidney, may experience flushing, abdominal pain, and nausea. These symptoms are classically relieved by positioning in antiflexion. Patients with homocystinuria may experience flushing in a malar distribution.

What is the Evidence?

Izikson, L, English III, JC, Zirwas, J. "The flushing patient: differential diagnosis, workup, and treatment". J Am Acad Dermatol. vol. 55. 2006. pp. 193-208.

(An extremely thorough review of the approach to the flushing patient, which includes an excellent discussion on the differential diagnosis, workup, and treatment of various etiologies of flushing.)

Heymann, WR. "Flushing, pheochromocytoma, and the dermatologist". J Am Acad Dermatol. vol. 55. 2006. pp. 1055-7.

(An excellent discussion on the flushing patient, with attention to an underlying etiology of pheochromocytoma. A thorough discussion of genodermatoses associated with flushing in this context is provided, as well as the underlying genetic aberrations and appropriate workup for these particular patients.)

Bains, SN, Hsieh, FH. "Current approaches to the diagnosis and treatment of systemic mastocytosis". Ann Allergy Asthma Immunol. vol. 104. 2010. pp. 1-10.

(An excellent and up-to-date review of mastocytosis, including a thorough discussion of different presentations of this entity and the appropriate workup and treatment guidelines for patients with various types of mastocytosis.)

Jacobson, TA. "A “hot” topic in dyslipidemia management - “how to beat a flush”: optimizing niacin tolerability to promote long-term treatment adherence and coronary disease prevention". Mayo Clin Proc. vol. 85. 2010. pp. 365-79.

(A good review of flushing in the setting of specific medications, especially niacin, which is a commonly used medication to treat dyslipidemia. A practical approach to treating flushing, a common and often disturbing and potentially debilitating side effect in these patients.)

Stinco, G, Piccirillo, F, Sallustio, M, Patrone, P. "Facial flush reaction after alcohol ingestion during topical pimecrolimus and tacrolimus treatment". Dermatology. vol. 218. 2009. pp. 71-2.

(A case report and discussion of this phenomenon, which can occur with use of a commonly prescribed steroid-sparing topical medication used in dermatology.)

Gorman, CR, White, SW. "Rosaceiform dermatitis as a complication of treatment of facial seborrheic dermatitis with 1% pimecrolimus cream". Arch Dermatol. vol. 141. 2005. pp. 1168.

(Similar to the above article, it provides case reports of this observed phenomenon.)

Yuraitis, M, Jacob, CI. "Botulinum toxin for the treatment of facial flushing". Dermatol. Surg. vol. 30. 2004. pp. 102-4.

(An interesting, although far from proven, application of botulinum toxin for the treatment of flushing. Until further evidence surfaces, or until additional studies are performed, it is not clear that this is an appropriate therapy for the flushing patient.)
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