Acrodermatitis Enteropathica

 

Introduction

Zinc is one of the most important trace elements in humans, playing a critical role in the function of more than 200 zinc-dependent metalloenzymes that regulate lipid, protein and nucleic acid synthesis and degradation. Zinc can be found in human breast milk, animal-based foods, shellfish, legumes and green leafy vegetables. There is evidence to suggest that zinc plays a role in enhancing wound healing and improving immune function and this may explain the poor wound healing and increased susceptibility to cutaneous infections that can be seen in patients with chronic zinc deficiency. Due to its antioxidant properties, zinc might protect the skin against UV-induced damage.

 

Etiology and Pathogenesis

Zinc deficiency may be either inherited, a form commonly referred to as AE, or acquired, and therefore referred to as AZD.

 

Acquired Zinc Deficiency (AZD)

AZD  occurs in older individuals and may result from states associated with inadequate intake, impaired absorption, or increased excretion, including pregnancy, lactation, extensive cutaneous burns, generalized exfoliative dermatoses, parenteral nutrition, anorexia nervosa, excessive sweating and diets high in mineral-binding phytate (Middle Eastern diets), and vegan diets. Of note, vegan diets can lead to low levels of long-chain n-3 (omega-3) fatty acids, calcium, vitamin D, and vitamin B_12.  Intestinal malabsorption syndromes, such as inflammatory bowel disease and cystic fibrosis, result in impaired intestinal absorption of zinc, whereas alcoholism and nephrotic syndrome result in increased renal zinc losses. Penicillamine has been reported to cause zinc deficiency in a patient with Wilson disease. Ornithine transcarbamylase deficiency has also been associated with zinc deficiency. Lastly, zinc deficiency can be seen in association HIV infection and chronic renal failure.

Acute AZD secondary to impaired absorption of zinc, inadequate intake or excessive intestinal or renal losses may result in a clinical picture that resemble AE and occurs also in adults.

A chronic or subacute form of zinc deficiency is also recognized. These patients often have zinc levels in the mildly deficient range (40-60 microgram/dl). Clinical manifestations include growth retardation in children and adolescents, hypogonadism in males, abnormal dark adaptation, dysgeusia, and poor appetite, poor wound healing and impaired mentation. Cutaneous manifestations, when present, are less striking and present predominantly as a psoriasiform dermatitis involving the hands and feet and occasionally the knees.

 

Acrodermatitis Enteropathica (AE)

The inherited form of zinc deficiency, AE, is a rare autosomal recessive disorder of zinc absorption. These infants have a defect in an intestinal zinc transporter, the human ZIP4 protein encoded on the SLC39A4 gene. Mutations in this gene prevent appropriate enteral zinc absorption.

AE classically presents during infancy on weaning from breast milk to formula or cereal, which have lower zinc bioavailability than breast milk. There is a form of AZD that may also present during infancy but, in contrast to AE, these infants become symptomatic while breast-feeding and improve after weaning to formula or table foods. Many of these reported infants have been premature, but cases have also been reported in full-term infants. The mothers of these infants have a presumed defect in mammary excretion of zinc into their breast milk, resulting in inadequate zinc intake in their infants. Breast milk zinc deficiency also occurs as a result of excessive maternal intake of calcium that the mother is taking in the belief that calcium supplements might mitigate postpartum depression. Measured breast milk zinc levels are significantly decreased and rebound to normal levels upon discontinuation of maternal calcium supplementation. Measurement of breast milk zinc levels is a useful tool and is diagnostic when less than 70 μg/dL.

 

Clinical manifestations

Skin findings are Identical in AZD and AE. Clinical manifestations usually appear within 1 to 2 weeks after weaning from breast milk, or at 4 to 10 weeks of age if bottle-fed. The classic triad of AE is diarrhea, alopecia and an acute eczematous and erosive dermatitis favoring periorificial (perioral, periocular, and anogenital) and acral areas (hands and feet), although this classical triad of symptoms occurs in only 20% of cases. The cutaneous findings are highly characteristic and often present initially as acrally distributed, patches and plaques of dry, scaly, sharply marginated and brightly red, symmetric, eczematous dermatitis. Over time, vesicles, bullae, pustules or erosions with a characteristic peripheral crusted border develop. The perioral eruption usually spares the upper lip, giving it an ‘U‐shaped’ or ‘horseshoe‐shaped’ appearance. There is usually a sharp demarcation between the affected area and normal skin. Diffuse hair loss on the scalp, eyebrows and eyelashes and graying of hair may occur. Patients also appear to be predisposed to systemic infections as a result of impaired cell-mediated immunity, and skin lesions become secondarily infected with Candida albicans and/or S. aureus. Red, glossy tongue, superficial aphthous-like erosions with secondary oral candidiasis may occur. There may be photophobia, irritable and depressed mood along with failure of growth. Children with AE whine and cry constantly. Other features include delayed wound healing, acute paronychia, nail ridging, and loss of nails, conjunctivitis, and blepharitis. Diarrhea may be prominent but is not seen in all cases. If untreated, the disease is fatal.

 

 

Clinical Features of Acrodermatitis Enteropathica

·       Eczematous and erosive dermatitis (Preferentially localized to periorificial and acral areas) ·       Alopecia ·       Diarrhea ·       Lethargy, irritability ·       Whining and crying ·       Super infection with Candida albicans and Staphylococcus aureus

 

 

Laboratory Testing

The histologic finding of epidermal necrosis plus low serum alkaline phosphatase and zinc levels point to the diagnosis.

A low plasma zinc level is the gold standard for diagnosing zinc deficiency. Use of contaminated needles, catheters, and sample tubes may lead to erroneously high measured zinc levels. Contact with collection tubes with rubber stoppers should be avoided as they may contain high levels of zinc. Normal plasma zinc levels range from 70 to 250 mcg/dL. Measurement of serum alkaline phosphatase—a zinc-dependent enzyme—is another useful and rapid indicator of zinc status, as alkaline phosphatase may be low-normal; serum alkaline phosphatase will increase with zinc supplementation, thus confirming the diagnosis.

 

Treatment

Zinc supplementation with either an enteral or parenteral formulation is appropriate. Clinical response is usually rapid, within 24 h after zinc replacement, the irritability, whining and diarrhea ceases and the infant's mood improves and within 1 to 2 weeks, severely infected and erosive skin lesions heal. Although several zinc formulations are available, the most commonly used enteral formulation is zinc sulfate. Zinc chloride is recommended for parenteral supplementation.

In children, 1–2 mg/kg of elemental zinc given as one to two daily doses is recommended for mild-to-moderate zinc deficiency and 3 mg/kg/day for AE. In adults, 15–30 mg of elemental zinc per day is usually sufficient in cases of AZD. Patients with persistent malabsorption syndromes and AE require lifelong zinc supplementation, along with regular serum zinc determinations. Patients with AZD may need variable levels of supplementation, depending on their underlying disease. Of note, excess zinc levels may interfere with copper metabolism.