Acrodermatitis Enteropathica From Zinc-Deficient Total Parenteral Nutrition

Comment

Background
Acrodermatitis enteropathica is a rare autosomal-recessive disorder of zinc metabolism characterized by skin lesions predominantly distributed in acral and periorificial sites as well as alopecia and diarrhea. Acrodermatitis enteropathica was first described by Brandt¹ in 1936 and later characterized by Danbolt and Closs² in 1942 as a unique and often fatal disease of unknown etiology. More than 30 years later, the link between zinc deficiency and AE was illustrated by Moynahan³ who demonstrated clinical improvement with zinc supplementation. It was not until 2002 that the molecular pathogenesis of hypozincemia in patients with inherited AE was described. Küry et al⁴ identified a mutation in the SLC39A4 gene responsible for encoding the Zip4 protein, a zinc transporter found on enterocytes, particularly in the proximal small intestine.^5,6 Classically, patients with inherited AE are children who present within days of birth or days to weeks after being weaned from breast milk to cow’s milk. The zinc in bovine milk is less bioavailable than breast milk, though both have similar total zinc concentrations, which results in the decreased plasma zinc levels seen in children with inherited AE.^5-8 Occasionally, children present before weaning due to decreased maternal mammary zinc secretion (lactogenic AE).^9,10

Clinical Presentation
Similar clinical findings are seen in patients with noninherited forms of zinc deficiency known as acquired AE. Acquired zinc deficiency may be broadly categorized as being from inadequate intake, deficient absorption, excess demand, or overexcretion.⁸ Such disturbances of zinc balance are most frequently seen in patients with restrictive diets, anorexia nervosa, intestinal bypass procedures, Crohn disease, pancreatic insufficiency, alcoholism, human immunodeficiency virus, and extensive cutaneous burns. Premature infants, mothers who are breastfeeding, and those dependent on TPN are at risk for developing acquired zinc deficiency.^7-9,11

Differentiating Characteristics
Both acquired and inherited AE present as erythematous or pink eczematous scaly plaques with the variable presence of vesicular or bullous lesions involving periorificial, acral, and anogenital regions. Early manifestations of AE may include angular cheilitis and paronychia. Alopecia and diarrhea are characteristics of later disease. In fact, the complete triad of dermatitis, alopecia, and diarrhea is seen in only 20% of cases.⁷Without treatment, patients may develop blepharitis, conjunctivitis, photophobia, irritability, anorexia, apathy, growth retardation, hypogonadism, hypogeusia, and mental slowing. Skin lesions frequently become secondarily infected with Candida albicans and/or bacteria.^5,7,11

Histopathology
Histopathologic examination of skin biopsy specimens from AE lesions demonstrates nonspecific findings similar to other deficiency dermatoses, such as pellagra and glucagonoma-associated necrolytic migratory erythema. Histology typically reveals cytoplasmic pallor with vacuolization and ballooning degeneration of keratinocytes, followed by confluent keratinocyte necrosis within the stratum granulosum and stratum spinosum of the epidermis.⁵ Confluent parakeratosis with hypogranulosis variably associated with neutrophil crust also is seen. Scattered dyskeratotic keratinocytes may be found within all levels of the epidermis. In resolving or chronic AE lesions, psoriasiform hyperplasia is prevalent, though necrolysis may be minimal or absent.^5,11

Diagnosis
Evaluation includes measurement of plasma zinc levels. Zinc levels less than 50 µg/dL are suggestive but not diagnostic of AE.⁵ Although plasma zinc measurement is the most useful indicator of zinc status, its utility in assessing the true total body store of zinc is limited. Plasma zinc is tightly regulated and only represents 0.1% of body stores.^5,6 Additionally, zinc levels may decrease in proinflammatory states.¹² Beyond zinc measurement, evaluation of alkaline phosphatase, a zinc-dependent enzyme, can provide useful diagnostic information.^5,6

Zinc and TPN
Patients on TPN are at a unique risk for developing zinc and other nutritional deficiencies. Because the daily recommended dietary allowance for zinc is low (8 mg daily for adult women and 11 mg daily for adult men)⁵ and the element is found in a wide variety of foods, maintaining adequate zinc levels is easily achieved in healthy individuals with normal diets. Kay et al¹³ described 4 patients on parenteral nutrition who developed hypozincemia and an AE-like syndrome within weeks of TPN induction. The authors described rapid and drastic clinical improvement after initiating zinc supplementation, accentuating the importance of including zinc as a component of TPN.^13,14 Brazin et al¹⁵ also reported a case of an AE-like syndrome from zinc-deficient hyperalimentation in a patient receiving TPN for short bowel syndrome. Chun et al¹⁶ described another case of acquired AE in a patient on TPN for acute pancreatitis. Both cases demonstrated prompt improvement of skin lesions after treatment with zinc supplementation. Other nutrient deficiencies may reveal themselves through similar dermatologic manifestations. For example, cases of scaly dermatitis secondary to the development of essential fatty acid deficiency from TPN formulations lacking adequate quantities of linoleic acid have been reported.Similar to our case, the resolution of skin lesions was seen after TPN was supplemented with the deficient nutrient.¹⁷ These cases exemplify the importance in considering deficiency dermatoses in the TPN-dependent patient population.

Conclusion

In our case, the development of skin lesions directly coincided with a recent removal of zinc from the patient’s TPN, which provided us with a unique opportunity to observe the causal relationship between decreased zinc intake and the development of clinical signs of acquired AE. This association was further elucidated by laboratory confirmation of low serum zinc levels and rapid improvement in all skin lesions after zinc supplementation was initiated.