Generalized hyperpigmentation as a dermatologic sentinel sign of illicit etomidate vaping: A brief case report

Dear Editor, In recent years, unregulated e-cigarette products – so-called “zombie vapes” – have emerged as an alarming public health issue. These illicit cartridges often contain synthetic psychoactive compounds, including etomidate, which can exert systemic toxic effects. Although etomidate-induced adrenal insufficiency is well recognized in anesthetic settings, its cutaneous manifestations remain largely unrecognized.1-4 We report a patient who developed generalized slate-gray hyperpigmentation, serving as a dermatologic sentinel sign of etomidate-associated primary adrenal insufficiency following chronic use of “zombie” vape cartridges. A 42-year-old man with no significant medical history presented with progressively worsening slate-gray hyperpigmentation involving the skin, nails, lips, and mucosa. The patient reported approximately 1 year of using “zombie” vape cartridges containing etomidate. Hyperpigmentation appeared after about 6 months of use and progressively worsened thereafter. Physical examination revealed generalized hyperpigmentation but no systemic illness. He denied fatigue, weakness, dizziness, weight loss, or gastrointestinal symptoms and reported no exposure to industrial chemicals, prescription or over-the-counter medications, or other substances aside from the “zombie” vapes. Differential diagnoses for generalized hyperpigmentation include adrenal insufficiency, thyroid dysfunction, hepatic or renal disease, heavy metal toxicity, vitamin deficiency, and acquired dermal macular hyperpigmentation (ADMH). Initial laboratory workup revealed normal serum electrolytes, including sodium and potassium, normal thyroid function tests (thyroid-stimulating hormone and free T4), as well as folate, Vitamin B3 (niacin), and vitamin B6 levels within normal ranges. Liver and renal function tests were within normal limits. Screening for mercury, arsenic, and lead was unremarkable. However, adrenocorticotropic hormone (ACTH) was markedly elevated at 1013 pg/mL, and serum cortisol was low at 5.187 μg/dL. Skin biopsy revealed only increased basal melanin. Although ADMH and adrenal insufficiency-related hyperpigmentation were considered, the absence of hallmark ADMH features – such as dermal melanophages, basal cell vacuolization, lichenoid interface change, or pigment incontinence – rendered ADMH unlikely Figure 1a.Figure 1: (a) Histopathologic examination showing increased melanin deposition in the basal layer of the epidermis (H and E, ×100). (b and c) Hyperpigmented macules on the intraoral mucosa and inner lips. (d) Hyperpigmentation over friction-prone areas. (e and f) Hyperpigmentation of the toenails and fingernails.These clinical, laboratory, and histological findings raised suspicion for adrenal insufficiency potentially related to toxic effects from synthetic substances. To distinguish between primary and secondary adrenal insufficiency, an ACTH stimulation test was performed by the endocrinology team. Serum cortisol levels measured at 1- and 2-h following ACTH administration failed to show a significant increase, confirming the diagnosis of primary adrenal insufficiency. Abdominal computed tomography demonstrated no remarkable abnormalities in either adrenal gland. After the patient discontinued use of the implicated e-cigarette products with the assistance of a family physician-supervised smoking cessation program and initiated glucocorticoid replacement therapy under the supervision of an endocrinologist, his hyperpigmentation and adrenal function gradually improved over a 6-month period. The glucocorticoid dosage was progressively tapered and eventually discontinued as adrenal function normalized. Follow-up evaluations showed no evidence of recurrence. Hyperpigmentation in adrenal insufficiency typically affects sun-exposed areas and regions of friction, including palmar creases, areolae, axillae, perineum, scars, and the umbilicus.5,6 Additional pigmentary changes, including irregularly distributed macules on the inner lips and buccal mucosa, were also observed.5,6 In our patient, all of these characteristic features were present. Aside from the aforementioned areas, the nails exhibited the most prominent pigmentary changes Figure 1b-f. Primary adrenal insufficiency may result from autoimmune, infectious, metastatic, hemorrhagic, or drug-induced causes.7,8 Based on imaging studies, laboratory data, and the clinical course, including treatment response Supplementary Figure 1, we were able to exclude autoimmune adrenalitis, infections, and metastatic infiltration, leaving drug-induced adrenal insufficiency as the most likely cause. Among pharmacologic agents, etomidate – which was the only agent the patient had contact with – is a well-recognized cause of adrenal insufficiency due to its reversible inhibition of 11 β-hydroxylase, a key enzyme in cortisol biosynthesis.1,2 Cortisol reduction leads to elevated ACTH, stimulating melanogenesis and diffuse pigmentation.5Supplementary Figure 1: Fingernail and oral mucosal pigmentation before and after 6 months of treatment. (a) Fingernail hyperpigmentation at baseline (arrowheads). (b) Marked improvement in nail color after treatment. (c) Hyperpigmented macules at the oral commissures at baseline (arrows). (d) Complete resolution of lip pigmentation after treatment.Recently, cases of adrenal insufficiency associated with e-cigarette use containing etomidate have been reported. These cases have presented with clinical features such as hypokalemia and virilization in female patients, both of which result from impaired adrenal hormone synthesis.3,4 This emerging evidence underscores the growing recognition of “zombie vaping” as a novel and important cause of adrenal dysfunction. To our knowledge, this is the first report from Taiwan to highlight a dermatologic clue indicative of adrenal dysfunction induced by illicit etomidate vaping. This case has certain limitations, including the absence of toxicological confirmation and the incomplete evaluation of potential heavy metal exposure due to institutional constraints. In addition, no data are available to define a cumulative inhaled etomidate level associated with skin hyperpigmentation. In summary, this case illustrates generalized hyperpigmentation as an early dermatologic diagnostic clue to toxic exposure from the increasingly widespread illicit use of vaping products. Clinicians should consider vaping-related toxicities in patients presenting with unexplained diffuse pigmentation and biochemical evidence of adrenal insufficiency. Ethics statement This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Chung Shan Medical University Hospital. Case number CS2-25121. Decision dated October 16, 2025. Written informed consent was obtained from the patient for the publication of this case report, including any relevant images. Data availability statement Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.