Underlying Etiologies of Cutaneous Flushing

As a dermatologic phenomenon, cutaneous flushing is a common complaint, signifying a broad range of etiologies. Flushing is defined as a local sensation of warmth in the face, head, neck, upper chest, and limbs, accompanied by erythema, both caused by increased cutaneous blood flow to the region.

Episodic flushing is generally a transient event, mediated by vasoactive causes or in reaction to certain drug therapies. If the attacks continue over months or years, then a fixed facial flushing may result that shows a constant telangiectases, as in rosacea. Over time, blood vessels in the area may expand with a cyanotic hue because of a slow flow of deoxygenated blood.¹

Most cases of cutaneous flushing are a result of fever, rosacea, menopause, and simple emotional blushing. Beyond these, a large range of other causes encompassing neurologic or vascular disorders, fish ingestion, psychiatric or anxiety disorders, or rare carcinomas and some very rare diseases may all be potential culprits. Flushing is upsetting and embarrassing to patients, who often seek treatment for it, but the potential for serious underlying mechanisms dictates a more thorough workup for patients who have indications of something more than a benign course. Differential diagnosis for all cases should be performed to rule out serious etiologies.

Benign Flushing

Benign, episodic flushing is what is most commonly seen in practice, caused by nonfebrile increases in temperature, heightened emotional states, exercise, and a wide range of foods and beverages. It affects women, who also frequently develop menopausal hot flushes, more than men. Ingredients in foods that may trigger flushing include tyramine, histamine, monosodium glutamate, aldehyde, nitrites, sulfites, and higher chain alcohols. Spicy foods are particularly associated with flushing because of capsaicin, a component of red peppers and cayenne pepper that causes a mild inflammatory effect. Hot beverages and alcohol are also known triggers.

Rosacea is a common, chronic flushing disorder that has a pattern of flares and remissions and may become progressive. The hallmarks are central facial flushing, erythema, visible blood vessels, papules, and pustules. Rosacea has 4 subtypes of increasing severity²:

• Erythematoangiectatic, presenting as persistent flushing and erythema with or without telangiectasia;
• Papulopustular, with persistent flushing and erythema, plus papules and pustules;
• Phymatous, involving thickening of the skin, irregular surface nodularities, and enlargement of blood vessels; and
• Ocular rosacea, the most serious form, which may involve inflammation of the eye and eyelid.

Treatments for rosacea include topical interventions such as metronidazole azelaic acid and ivermectin. In addition, oral medications including doxycycline, tetracycline, minocycline, and isotretinoin are good options for the management for the papulopustular form, whereas topical brimonidine is used for erythema. Low-quality evidence supports the use of laser light therapy as a treatment for telangiectasia and cyclosporine for ocular rosacea.^2,3

Climacteric flushing, also known as “hot flushes,” affects 50% to 85% of women during the perimenopausal years, brought on by fluctuations of estrogen levels in the blood.^1,2 The symptoms are sudden and triggered by stress, alcohol, caffeine, hot drinks, and sudden temperature changes. The frequency varies from every few days to multiple times in a single hour, often followed by chills and anxiety.² The symptoms are often very distressing and may produce insomnia, fatigue, and irritability. Therapies may include clonidine (an alpha-adrenergic agonist) to reduce the vascular reactivity that precipitates attacks. In more severe cases, flushing can be treated with hormone replacement therapy to reduce fluctuations. Ultimately, this type of flushing resolves with time as hormone levels begin to stabilize. Most patients (75%) will stop having hot flushes after 5 years, although for some, symptoms can continue for up to 30 years.²

Flushing Associated With Serious Underlying Conditions

Systemic Conditions

Several conditions, including hyperthyroidism, dumping syndrome, and superior vena cava obstruction, may also produce symptoms of flushing. Neurologic causes are particularly broad and include brain and spinal cord tumors, migraine and cluster headache, trigeminal neuralgia, diabetic neuralgia, Parkinson disease, and multiple sclerosis, among many others.⁴

Malignant Causes

A number of malignancies may present with signs of flushing that do not appear to have benign physiologic causes. Flushing that involves larger portions of the body or areas other than the head and neck region, and episodes that do not quickly resolve themselves in minutes, are reasons to suspect serious malignant causes such as mastocytosis, medullary thyroid carcinoma, pheochromocytoma, renal cell carcinoma, and various rare carcinomas.⁵

Presentation in these conditions often varies from the standard benign symptoms that are generally limited to the face, head, and neck.⁵ Unilateral face or body flushing generally signals a neurologic origin, whereas widespread flushing that is deep red or brown in color with a cyanotic facial flushing points to carcinoid etiologies.⁵ Medullary thyroid carcinoma may present in a wider region including the face, neck, chest, and arms.⁵

Work-up for Nonbenign Causes

In any presentation that is not clearly a result of benign causes (fever, rosacea, climacteric), further laboratory workup is strongly recommended and depends on the suspected origins.⁵ For neurologic causes, imaging modalities are best, whereas 24-hour urinanalyses for various hormones and serum tryptase are important to diagnosing carcinoid causes, and measurement of calcitonin is used to rule in or out medullary thyroid carcinoma.

References

1. Izikson L, English JC, Zirwas MJ. The flushing patient: differential diagnosis, workup, and treatment. J Am Acad Dermatol. 2006;55(2):193-208.
2. İkizoğlu G. Red face revisited: flushing. Clin Dermatol. 2014;32:800-808.
3. Layton AB. Pharmacologic treatments for rosacea. Clin Dermatol. 2017;35:207-212.
4. Sadeghian A, Rouhana H, Oswald-Stumpf B, Boh E. Etiologies and management of cutaneous flushing: nonmalignant causes. J Am Acad Dematol. 2017;77:405-414.
5. Sadeghian A, Rouhana H, Oswald-Stumpf B, Boh E. Etiologies and management of cutaneous flushing: malignant causes. J Am Acad Dematol. 2017;77:391-402.