The flush beyond the blush
Consider underlying malignancies
by John Kraft, MD and Charles Lynde, MD
Vol.16, No.01, January 2008

The term “flushing” refers to a transient reddening or erythema of the skin, which is most often caused by emotional blushing, hyperthermia, fever, menopause or rosacea. There are also some rare and serious conditions, however, that can present with flushing — these include fish poisoning and certain carcinomas.

Physiologically, flushing is a visible sign of increased cutaneous blood flow occurring as a result of vascular smooth muscle relaxation, mediated by vasomotor nerves or by agents circulating in the blood. “Blush areas” such as the face, ears, neck, upper chest and upper arms have a relatively high degree of cutaneous vasculature. Autonomic neural-mediated flushing is also called wet flushing, as it’s associated with sweating. Conversely, when there’s no sweating or sensory change, i.e. dry flushing, the reddening is most likely due to a direct vasodilator-mediated mechanism triggered by an exogenous or endogenous agent.

Flushing can be episodic or constant. When it’s constant, it can lead to visible skin changes such as telangiectasias, fixed facial redness and areas of cyanosis due to cutaneous blood vessel enlargement.

Ruling out rosacea

One of the most common causes of flushing is rosacea, a skin disease (see Skin Sense, of Parkhurst Exchange March 2005) that also presents with erythema, telangiectasias, papules and pustules. In addition, look for phymatous changes, such as thickening of the nose, and ocular symptoms. Flushing may be the only manifestation, though, and follow-up is needed to monitor progression.

Fish poisoning

Elevated histamine levels resulting from bacterial metabolism in fish meat can lead to scombroid fish poisoning, which might cause flushing. Other symptoms include urticaria, palpitations and abdominal complaints. Treatment is similar to the management of anaphylaxis, i.e. with antihistamines, epinephrine and systemic corticosteroids.

Malignancies

There are a number of malignancies that may present with flushing, for instance, renal cell carcinomas or pancreatic tumours. Medullary thyroid carcinoma, a malignant tumour of parafollicular C cells, can also cause this symptom in the context of a thyroid nodule.

Then there’s the carcinoid syndrome, which occurs in about 10% of patients with carcinoid tumours and manifests with flushing, gastrointestinal (GI) hypermotility and right-sided heart failure. The underlying tumour is made up of neuroendocrine cells and is most often found in the small bowel, proximal colon, appendix or pulmonary bronchi. It secretes many vasodilators, including serotonin, 5-hydroxytryptamine (5-HT), substance P, histamine and catecholamines. Treatment, for example with octreotide, aims at reducing the secretion of vasoactive mediators.

Mastocytosis

Mastocytosis refers to a spectrum of diseases characterized by tissue infiltration with mast cells, ranging from benign skin lesions to mast cell leukemia. With this condition, flushing is often accompanied by pruritus, urticaria and hypotension. GI symptoms include diarrhea, nausea and vomiting. Treat with H1 and H2 blockers, topical steroids, psoralen in combination with ultraviolet A light therapy, and imatinib for systemic disease.

Neuroendocrine tumours

Finally, flushing in association with palpitations, tachycardia, pallor and hypertension — sometimes resembling panic attacks — may indicate pheochromocytoma, a tumour of chromaffin cells in the adrenal medulla, producing catecholamines.

Neural-mediated flushing

In this variant, vasodilation results from autonomic dysfunction (Table 1). Nerve fibres release substance P, which causes widening of the blood vessels with pain, burning and numbness. Neuropathic pain can be treated with low-dose tricyclic antidepressants and anticonvulsants.

Blushing

One of the most common presentations of neural-mediated flushing is blushing, i.e. a reaction associated with anxiety or embarrassment. It’s usually triggered by emotion, but temperature changes, exercise, hot beverages and spicy foods may also be implicated.Treatment includes behavioural therapy and agents that lessen the vascular response to anxiety, such as nadolol.

Menopausal flushing

There’s also menopausal flushing, which affects the majority of menopausal women. Episodes are associated with perspiration and last up to 5 minutes, occurring 15-20 times per day for months to years. The hot flushes are caused by estrogen fluctuations, and central adrenergic and opioid pathways may also play a role. You can treat with clonidine, a central acting alpha-2 agonist that reduces the frequency and severity of episodes. It’s often dosed at 0.1 mg orally, divided into 2 doses per day. If this amount isn’t effective, patients rarely respond to higher doses, but adding the opioid antagonist naloxone may be helpful.

Approach

Take a careful history and distinguish between wet and dry flushing. Check patients with dry flushing for pain sensation — an altered response suggests antidromic sensorineural flush, e.g. trigeminal neuralgia or migraine. If the pain sensation is normal, the history may reveal exogenous triggers such as alcohol, drugs or foods (see list below). Next, consider endogenous causes, i.e. check for associated symptoms of systemic disorders. In difficult cases, have the person keep a diary where they record activities, medications, food, beverages and associations between flushing and other symptoms. On exam, look for manifestations of rosacea and relevant systemic causes of flushing, and order the appropriate investigations (see Table 1).

Patients should avoid dietary triggers such as hot liquids and vasodilatory agents. Sipping ice water or sucking on ice chips can hasten resolution of flushing episodes, but there’s no broad-spectrum anti-flushing treatment.

Charles Lynde, MD, FRCP(C) is an assistant professor of dermatology at the University of Toronto.

John Kraft, MD, is in his second year of the Dermatology Residency Program at the University of Toronto, Ontario.

Exogenous agents that can induce flushing
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