Raising a toast to advances in treating alcohol-induced flushing

By Warren R. Heymann, MD
November 11, 2020
Vol. 2, No. 45

Whether with pride or embarrassment, we have all blushed. Also known as flushing, the process is defined as a visible reddening of the skin accompanied by a sensation of warmth, characteristically affecting the face, ears, neck, and upper chest. Of the myriad causes of flushing (fever, hyperthermia, emotions, menopause, medications, food, hypersensitivity reactions, rosacea, hyperthyroidism, dumping syndrome, superior vena cava syndrome, and neurologic disorders), alcohol is a major precipitant. (1)

Aldehyde dehydrogenase 2 (ALDH2) deficiency is very common, affecting 8% of the world population, with the highest prevalence (35%–45%) in people of East Asian descent. Mutations in ALDH2 are responsible for the Asian flush syndrome (AFS), characterized by facial flushing, headache, nausea, dizziness, and cardiac palpitations after consumption of alcoholic beverages.

The syndrome is caused by elevated blood acetaldehyde levels resulting from reduced ALDH2 enzymatic activity of the mutant protein. Importantly, the ALDH2*2 variant allele is associated with a significant increase in the risk of upper aerodigestive tract cancer of the oral cavity, pharynx, larynx, and esophagus. (2)

There have been some intriguing case reports of alcohol-induced flushing in patients who presumably do not have AFS.

Sabatar-Abad et al reported the case of a 66‐year‐old woman with facial vitiligo, with no history of alcohol‐related facial flushing, who instituted treatment with topical tacrolimus 0.1%. After 3 months she reported self‐limited episodes of facial erythema, lasting up to an hour, accompanied by a burning sensation. Symptoms were limited to the treated regions, appearing 20 min after drinking alcoholic beverages. (3) This reaction has been reported in approximately 6% of patients using tacrolimus for atopic dermatitis, eyelid eczema, and psoriasis. Upon its discontinuation, the reaction to alcohol resolves within a couple of weeks. The pathomechanism of this phenomenon is unknown. (4)

A 19-year-old woman with atopic dermatitis refractory to topical steroids and topical calcineurin inhibitors, was subsequently treated with dupilumab. Although her eczema improved rapidly, after 16 weeks she reported the onset of an adverse event — drinking alcohol would always cause a facial flush (with lesser involvement of the neck and décolleté) within 3 to 4 minutes. Symptoms would disappear spontaneously after about 30 min. It was recommended that she continue dupilumab and avoid alcohol. The pathophysiology of this reaction with dupilumab is an enigma. (5)

Topical α-agonists are utilized in rosacea to diminish the persistent facial erythema caused by fixed dilatation of superficial skin vasculature. Both brimonidine 0.33% gel (predominantly an α-2 receptor agonist) and oxymetazoline 1% cream (predominantly an α-1 receptor agonist) are FDA approved for topical therapy of persistent facial erythema of rosacea, with both agents demonstrating efficacy and safety in clinical studies. Up to 20% of patients treated with brimonidine 0.33% gel experience reversible worsening of facial erythema, usually presenting as either paradoxical erythema shortly after application or rebound erythema after eventual loss of pharmacologic effect or drug discontinuation. For oxymetazoline 1% cream, only a low to negligible risk of worsening of facial erythema or rebound has been observed. (6)

Regarding treatment of AFS, Yu et al performed a randomized, placebo-controlled, double-blind split-face clinical trial of 20 individuals of East Asian descent comparing brimonidine to placebo. Brimonidine decreased erythema, following the ingestion of alcohol, by an average of 2.1 and 1.7 points as evaluated by the clinician and the patient, respectively, on an erythema grading scale of 0 to 4 points. The authors demonstrated that brimonidine gel is effective in reducing the alcohol-induced facial erythema of AFS. Because of the risk of aerodigestive cancers in patients with AFS, the authors proposed that even with improvement of facial flushing utilizing brimonidine in these patients, clinicians must remind patients of associated risks, and emphasize that patients not exceed moderate consumption of alcohol. (7) It would be intriguing to perform the same study using oxymetazoline.

Matsumura et al hypothesized that a one-time administration of an adeno-associated virus (AAV) gene transfer vector expressing the human ALDH2 coding sequence would correct the deficiency state. This experiment was performed in mice. Following acute ethanol ingestion, untreated ALDH2-deficient mice had elevated acetaldehyde levels and performed poorly in behavioral tests. In contrast, treated mice had lower serum acetaldehyde levels and improved behavior. The authors concluded that in vivo AAV-mediated ALDH2 therapy may reverse the deficiency state in ALDH2*2 individuals, eliminating the AFS and reducing the risk for associated disorders, including malignancies. (2)

AFS, and other alcohol-related flushing dermatoses, adversely affects patients’ quality of life. I salute the researchers who are admirably sorting this out — cheers!

Point to Remember: The alcohol-induced flushing syndrome is common in patients of Asian descent. Topical brimonidine may be a reasonable agent in combating this disorder that causes psychosocial aggravation.

Our Experts’ Viewpoint

Adam Friedman, MD
Professor and Interim Chair of Dermatology
Director, Residency Program
Director, Translational Research
Director of Supportive Oncodermatology
George Washington University School of Medicine and Health Sciences

I truly enjoyed the innovative study by Yu et al. which called upon one of our greatest skills, off-label medication use, to manage a benign yet belligerently debilitating outcome from finishing the week, taking a load off, or my favorite, saying it’s noon somewhere. Even with the relatively clear understanding of the genetic underpinnings and metabolic abnormalities that lead to ethanol (ETOH) induced flushing in specific populations, could there be further complexity? When I think of vasodilation +/- edema, I always consider our friend the mast cell. This chiclet gum-like granulocyte, chocked full of heparin, histamine, and a whole lot of proteases, can degranulate on a whim to induce the wheal and flare of urticaria, among other clinical entities. I imagine in the right clinical context, or with the right phenotype, this response could mimic flushing. Considering alcohol: Mast cells have been identified as a key player in and drive of tissue damage associated with chronic alcohol use (J Clin Exp Pathol 2015, Vol 5(2): 218). Alcohol consumption has also been linked to inducible generalized and even segmental urticaria. Three mechanisms have been proposed: 1. The direct action of ETOH on mast cells causing them to degranulate; 2. Allergenic potential of ETOH metabolites; and 3. The activation of prostaglandin and endogenous opioid receptors. The subject raises more questions than answers, although my interpretation is that for those suffering from this malady, who do not respond to topical vasoconstrictors, pretreatment with a mast cell stabilizer such as cromolyn or ketotifen could be useful, potentially in combination with oral antihistamines (although this just covers for one of several mast cell degranulated products). Wouldn’t that make for an interesting study and even more so the call for study participants?

Dr. Friedman had disclosed financial relationships with the following to the AAD at the time of publication: AbbVie, Aclaris Therapeutics Inc., Allergan, Inc., Amgen, Bayer, Biogen, Dermira,Encore Dermatology, Inc., Eli Lilly and Company, Exeltis, Galderma USA, Hoth Therapeutics, IntraDerm Pharmaceuticals, Janssen Biotech, Johnson and Johnson Consumer Products Company, La Roche-Posay Laboratorie Pharmaceutique, Medscape, Menlo Therapeutics,Novartis, Oculus innovative Sciences, Inc., Orlando Dermatology Aesthetic & Clinical (ODAC), Ortho Dermatologics,Pfizer Inc., Promius Pharma, LLC, Regeneron,Sanova Works, Valeant Pharmaceuticals International, Valeant Pharmaceuticals North America LLC. Full disclosure information is available at coi.aad.org.

1. Sadeghian A, Rouhana H, Oswald-Stumpf B, Boh E. Etiologies and management of cutaneous flushing. J Am Acad Dermatol 2017; 77: 391-402.

2. Matsumura Y, Stiles KM, Reid J, Frenk EZ, et al. Gene therapy correction of aldehyde dehydrogenase 2 deficiency. Mol Ther Methods Clin Dev 2019; 15: 72-82.

3. Sabater-Abad J, Matellanes-Palacios M, Parilla FM. Image gallery: Interaction between alcohol and topical tacrolimus as a cause of facial flushing. Br J Dermatol 2019; 180: 144.

4. Knight AK, Boxer M, Chandler MJ. Alcohol-induced rash caused by topical tacrolimus. Ann Allergy Asthma Immunol 2005; 95: 291-292.

5. Herz S, Petri M, Sondermann W. New alcohol flushing in a patient with atopic dermatitis under therapy with dupilumab. Dermatol Ther 2019; 32: e12762.

6. Del Rosso JQ. Del Rosso JQ. Topical α-1 Agonist Therapy for Persistent Facial Erythema of Rosacea and the Addition of Oxymetazoline to the Treatment Armamentarium: Where Are We Now? J Clin Aesthet Dermatol 2017; 10: 28-32.

7. Yu WY, Lu B. Tan D, Aroyan C, et al. Effect of topical brimonidine on alcohol-induced flushing in Asian individuals: A randomized clinical trial. JAMA Dermatol 2019; Dec 4 [Epub ahead of print].

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