Acrodermatitis enteropathica
Acquired or inherited, a little zinc goes a long way
by John Kraft, MD and Charles Lynde, MD
Vol.18, No.09, October 2010

Zinc is an essential mineral necessary for normal growth and development. It’s needed for more than 200 metalloenzymes found throughout the body and plays important roles in lipid, protein, and nucleic acid synthesis and degradation. It’s necessary for the immune system, wound repair, cardiovascular health, reproduction and neuropsychiatric functioning.

Zinc is accumulated in utero, especially in the third trimester, then by diet. It’s absorbed in the proximal small intestine and excreted in the distal small intestine. Although formula contains more zinc than breast milk, the zinc in breast milk has a much greater bioavailability. Adults have approximately 2-3 grams of zinc stored in skin, muscles, bone and the prostate gland with a daily requirement of 15 mg per day.

Zinc deficiency can be inherited — acrodermatitis enteropathica — or acquired. Acrodermatitis enteropathica is a rare hereditary, autosomal recessive condition that results in impaired zinc absorption. The disorder results from a defective SLC39A4 gene that encodes ZIP4, an intestinal zinc-specific transporter-like protein. It presents within 1 to 2 months in bottle-fed infants and 1 to 2 weeks after weaning from breast milk with a quick appearance of the clinical features.

Non-hereditary or acquired zinc deficiency has a more insidious onset, with fewer severe clinical features. It can occur at any age, depending on the cause (Table 2). In some premature babies, the mother’s milk may not contain adequate zinc levels and the baby may become zinc deficient. In certain places, e.g. the Middle East, where there are high levels of phytates, a zinc chelating agent in the soil, zinc deficiency can be endemic. It typically presents in adolescents with short stature and delayed puberty.

Clinical features

The clinical features of zinc deficiency involve the skin, gastrointestinal tract, central nervous system, eyes and development. The classic triad involves skin findings, alopecia and diarrhea. Lesions on the skin are typically seen in a periorificial and acral distribution. Erythematous, well-demarcated, scaly plaques, with erosions and vesicles, are seen around the mouth, nares, eyes and genitals. There can be desquamation on the fingertips. Superinfection with bacteria and candida is common, as well as poor wound healing. Nail changes include paronychia and Beau’s lines.

Alopecia can be total and usually occurs after the skin findings. It begins with diffuse thinning. Diarrhea can be the presenting symptom. Other gastrointestinal features include loss of taste, loss of smell and anorexia.

Differential diagnosis

The differential diagnosis depends on the location of the lesions and age of the patient. Consider other nutritional deficiencies, e.g. biotin, riboflavin. For facial lesions in the infant, consider atopic dermatitis, seborrheic dermatitis and neonatal subacute cutaneous lupus. For lesions in the skin folds, consider atopic dermatitis, seborrheic dermatitis, irritant and allergic contact dermatitis, candida, erythrasma, and rule out Langerhans cell histiocytosis.

In adults, similar lesions can be seen with many of the above conditions, as well as Hailey-Hailey disease, Darier’s disease, necrolytic migratory erythema and pemphigus.

Investigations

Diagnosis is usually suspected clinically and treatment is initiated immediately to prevent complications. Investigations include confirming the diagnosis with a plasma zinc level. Plasma zinc levels are difficult to obtain accurately as samples are easily contaminated. It requires a stainless steel needle, either a plastic syringe or acid-washed glass tube without a rubber stopper, and a morning fasting sample. Results usually take two weeks. Zinc levels can also be assessed from hair, saliva or urine, but this is rarely done. A quicker screen is to look for low levels of zinc-dependent enzymes such as alkaline phosphatase.

A skin biopsy can help distinguish between other papulosquamous skin diseases (diseases that have well-demarcated, red, scaly plaques — psoriasis is the classic example). The biopsy shows a pale epidermis with necrotic keratinocytes, and isn’t specific to zinc deficiency. Similar findings are seen in other nutritional deficiencies, necrolytic migratory erythema, glucagonoma syndrome and necrolytic acral erythema.

Treatment

The mainstay of treatment involves zinc supplementation. Iodoquinol (Diodoquin), an anti-parasitic medication, was historically used to treat acrodermatitis enteropathica before it was known to be due to zinc deficiency, but is no longer used due to risk of optic atrophy and blindness. It was thought to enhance zinc absorption. Consider offering supportive care such as protective ointments, and anti-bacterial and anti-yeast agents, if there’s any superinfection.

Zinc is available in oral — zinc sulphate — and intravenous — zinc chloride forms. One to 3 mg/kg/day of elemental zinc is recommended. A 220 mg tablet of zinc sulphate has 55 mg of elemental zinc. The effect is usually dramatic, with resolution of the irritability and diarrhea within 24 hours, and skin findings resolve by two weeks. Acrodermatitis enteropathic requires life-long zinc supplementation, while in non-hereditary forms the duration depends on the underlying cause.

Zinc therapy is not entirely benign. It can be complicated by nausea, vomiting and gastric bleeding. Zinc supplementation can lead to low copper levels resulting in microcytic anemia, neutropenia and immune dysfunction. Routine monitoring should include plasma zinc level, copper level, complete blood count and differential, and testing for fecal occult blood.

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

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

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