Continuing Education Activity

Chloracne is an uncommon acneiform dermatosis caused by exposure to halogenated aromatic compounds. It represents a hallmark cutaneous manifestation of systemic toxicity. The malar cheeks, postauricular skin, axillae, and groin are commonly affected areas. Severity follows a typical dose-response relationship curve. This activity reviews the presentation, evaluation, and management of chloracne and highlights the role of an interprofessional team approach to the care of affected patients.

Objectives:

• Review the etiology of chloracne.
• Describe the appearance and classical distribution of chloracne.
• Explain the treatment of chloracne.
• Identify how to improve care coordination among interprofessional team members and optimize outcomes for patients affected by chloracne.

Introduction

Chloracne is an acneiform eruption caused by exposure to halogenated aromatic compounds. Dioxin is recognized as the most significant environmental chloracnegen [1][2] but several are known as endocrine-disrupting compounds (EDCs), such as polychlorinated biphenyls (PCBs).[3] Agent Orange is an infamous defoliant employed in the Vietnam War known to include traces of dioxin. Typical lesions include cysts, nodules, pustules, and open and closed comedones. The malar cheeks, postauricular skin, axillae, and groin are classically affected areas.[2] Severity follows a typical dose-response relationship curve; there may be multisystem impairment of the eyes, liver, endocrine, and nervous systems with high-level exposure. Chloracne is also known as MADISH (Metabolizing Acquired Dioxin Induced Skin Hamartomas).[4]

Etiology

Routes of exposure include direct skin contact, ingestion, and inhalation. Most cases are related to occupational[5] or accidental exposure; however, the poisoning of Ukrainian President Victor Yushchenko is a notable case involving a purposeful poisoning using dioxin. Chloracnegens are fat-soluble and persist in the body fat, as well as skin, for a long period after exposure.

Chloracne is caused by exposure to halogenated aromatic hydrocarbons found in:

• Fungicides
• Herbicides
• Insecticides
• Wood preservatives

Chemicals responsible for inducing chloracne include:

• Chlornaphthalene
• Chlorobenzene
• Polychlorobiphenyls (PCBs)
• Polychlorinated dibenzo-p-dioxins (PCDDs)
• Polychlorinated dibenzofurans (PCDFs)
• Pyrazole derivatives
• Chlorophenol contaminants
• Trifluoromethyl

Epidemiology

Chloracne is a rare skin condition that is most often reported as a hazard of occupational exposure and may be seen in chemical production workers, and those who handled, applied, or were exposed to 2,3,7,8-TCDD-contaminated pesticides.[5] Outbreaks have occurred with accidental mass exposures and at least one well-known individual has been targeted by poisoning. The first documented human exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD)-contaminated chemicals was reported in 1949 after a trichlorophenol reactor exploded in Nitro, West Virginia; communities have been affected by contaminated oil in Missouri and industrial waste in Seveso, Italy.[6] The largest reported incident occurred in Japan in 1968 and involved approximately 1,600 victims.[2] During the Vietnam War, Agent Orange was used widely, but the true prevalence of chloracne in Vietnam veterans is not known. Today, the use of polyhydrocarbons containing dioxin is restricted.[7]

Pathophysiology

Chloracne is an acne-like condition that occurs due to the persistence of toxic chemicals and their metabolites. Toxins accumulate within the sebaceous glands and alter their normal physiology from oil-producing glands into the cyst-like structures (hamartomas) of chloracne.[8] These changes take place through activation of the aryl hydrocarbon receptor (AHR) which is expressed in keratinocytes and sebocytes, accelerating epidermal terminal differentiation (keratinization) and converting sebocytes toward keratinocyte differentiation. [9][10] Specimens from the epidermis and cyst epithelium of MADISH patients demonstrates a strong expression of small proline-rich protein 2 (SPRR2), secretory leukocyte peptidase inhibitor (SLPI), epigen (EPGN), and the nuclear factor erythroid-derived 2 like 2 (NRF2) target NAD(P)H dehydrogenase, quinone 1 (NQO1).[11]

Systemically, chloracnegens can act as endocrine-disrupting compounds (EDCs), in which they behave like other endogenous hormones such as estrogens, progesterone, and androgens. They can also manipulate numerous receptors, like those related to retinoids or aryl hydrocarbons, resulting in overactivation and perturbations of the normal metabolic pathways. As a result, EDCs can lead to thyroid dysfunction, reproductive issues (cryptorchidism, hypospadias, testicular cancer, and female precocious puberty), leukemia, brain tumors, neurobehavioral disorders, type 2 diabetes, and obesity.[3]

Histopathology

The most distinguishing histopathologic feature of chloracne is the glaring lack of sebaceous glands.[4] There are often epidermal cysts that may be superficial with an open punctum or dermal cysts.

History and Physical

The course of systemic symptoms and skin changes varies based on the duration and level of toxic exposure. If massive exposure occurs, symptoms may appear within days. Chloracne lesions may not appear for weeks to months after exposure.

Acute, high-level exposure to halogenated aromatic compounds may cause the following systemic symptoms:

• Gastrointestinal distress (nausea, vomiting, diarrhea)
• Liver dysfunction
• Pancreatitis
• Neuropathy
• Joint pain

Skin lesions appear on the cheeks and postauricular skin and may progress into the axillae and groin. They may also involve the shoulders, chest, back, and abdomen or in very advanced cases, extend to the extremities. The skin may first appear excessively oily before the typical lesions of chloracne arise including:

• Open and closed comedones (blackheads and whiteheads)
• Nodules and cysts
• Pustules

Other cutaneous and mucosal problems seen with chloracne include:

• Palmar and/or plantar hyperhidrosis (excessive sweating of the palms and/or soles)[2]
• Porphyria cutanea tarda (pigmentation, increased hair growth, and blisters on exposed skin) [2]
• Hypertrichosis of body hair
• Hyperpigmentation of skin, hair, or nails
• Conjunctivitis, hyperpigmentation of the conjunctival mucosa, and enlargement of meibomian glands [12] [2]

Evaluation

A targeted history and physical exam are vital for a correct diagnosis. Toxicologic screenings for halogenated aromatic hydrocarbons may be performed but there is conflicting evidence as to their reliability. In the past, the measurement of polyhydrocarbons routinely was made in the blood and urine. In a group of individuals exposed to 2,3,7,8-TCDD, chloracne, elevations in GGT and triglycerides, as well as alterations in FSH and LH correlated to serum 2,3,7,8-TCDD levels.[6] However, due to differences in individual sensitivities to dioxin and its related chemicals, and because these substances can be concentrated within adipose and skin structures, it is challenging to diagnose chloracne solely based on serum toxic equivalent (TEQ) values. [4]

Biopsies of affected skin may show a reduction of the normal sebaceous gland density and skin hamartomas. Immunohistochemistry can be carried out on biopsy specimens to assess the gene expression (i.e. CYP1A1).[13]

Treatment / Management

Once chloracne is diagnosed, the primary action is to prevent further exposure to the chemical source, which in many cases will result in improvement of the lesions. If lesions persist for a long time despite the elimination of further toxin exposure, treatments used for acne vulgaris such as topical retinoids, oral antibiotics or isotretinoin may be considered. Comedones may be expressed and cysts may be excised. Recently, a small cohort of Japanese patients with dioxin-related sequelae for 30-40 years was treated orally with a cinnamaldehyde-containing antioxidant called Keishibukuryogan. Treatment with this herbal medicine, which exhibits AHR–CYP1A1 inhibition and NRF2 activation, resulted in improvement in the patients' chloracne and associated systemic symptoms.[14]

Patients with chloracnegen exposure history must be followed longitudinally because the toxic exposure may also impact other organs than the skin and may be linked to various malignancies.

Differential Diagnosis

• Acne vulgaris
• Favre-Racouchot syndrome (also known as solar or senile comedones and nodular elastosis with cysts and comedones)
• Folliculitis
• Dilated pore of Winer
• Epidermal inclusion cyst
• Milia
• Folliculotropic mycosis fungoides
• Nevus comedonicus

Prognosis

The severity and duration of chloracne lesions correlate to toxin exposure time and levels. Once the exposure has been isolated and removed, lesions will generally improve without further intervention, although this may take years.

Complications

Chloracne is associated with a variable amount of permanent scarring. Lesions on the malar cheeks and postauricular skin tend to persist longer than those localized elsewhere on the body.[2] 

Immunotoxicity, namely immunosuppression[15], and developmental effects may occur over long periods of exposure to dioxin and dioxin-like compounds.[16] Malignancies linked to chloracnegen exposure include non-Hodgkin lymphoma, soft-tissue sarcomas (such as dermatofibrosarcoma protuberans, and leiomyosarcomas)[17], and nonmelanoma skin cancer.[18]

Deterrence and Patient Education

Patients with occupational risk factors such as exposure to herbicides, insecticides, fungicides, wood treatments, or those who may have been exposed to Agent Orange should be counseled on systemic and cutaneous signs and symptoms associated with chloracne. The data for an association with other health problems such as congenital anomalies are conflicting;[2] however, it would be prudent to educate both partners on the potential for congenital anomalies. Patients can be provided with reassurance that in most cases, lesions and systemic symptoms tend to spontaneously improve slowly over time once there is no further chemical exposure.

Pearls and Other Issues

Other health problems associated with chloracne include:

• Abnormal liver function
• Fatigue and sleep disturbance
• Transient peripheral neuropathy
• Encephalopathy, leading to poor concentration or depression
• Hyperlipidemia (particularly increased triglycerides) [2]
• Impotence
• Type 2 diabetes

Patients should undergo regular full body skin exams as well as blood work including a CBC with differential, liver function tests, hemoglobin A1c and serum cholesterol to monitor for cutaneous malignancies, lymphoma, liver dysfunction, type 2 diabetes, and hyperlipidemia.

Enhancing Healthcare Team Outcomes

Chloracne is a rare skin disorder but when it presents, it is best managed by an interprofessional team that includes poison control, a dermatologist, a biohazard expert, and an internist. The source needs to be identified as rapidly as possible to help minimize a public health disaster. Chloracne is the hallmark cutaneous feature and may best be treated by a dermatologist when recalcitrant. However, regular physicals and blood work monitoring should be carried out by an internist to identify other possible systemic sequelae.