Acrodermatitis Enteropathica


Article Author:
Soumya Jagadeesan


Article Editor:
Feroze Kaliyadan


Editors In Chief:
William Gossman


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
12/5/2018 10:05:08 AM

Introduction

Acrodermatitis enteropathica (AE) is an inherited form of zinc deficiency caused by a defect in the absorption of zinc. Zinc is a very important micronutrient, a component of more than two-hundred metalloenzymes, and essential for the proper functioning of the various metabolic and biochemical pathways of the body. AE results from mutations in the zinc transporter gene SLC39A4 (solute carrier family 39 member A4), leading to improper enteral zinc absorption. AE was first described by Brandt in 1936 and later identified as a distinct disease by Danbolt and Closs. Zinc deficiency acquired secondary to malabsorption syndromes, liver or kidney disease, dietary habits, and iatrogenic causes also can present with clinical features simulating AE.[1][2][3]

Etiology

The gene SLC39A4 on chromosome 8q24.3 codes for the zinc-ligand binding protein ZIP 4, zinc or iron-regulated transporter-like protein. It is a histidine-rich transmembrane protein that works as a zinc uptake protein to transport zinc ions from the cell exterior or lumen into the cytoplasm, where they are available for other proteins. Therefore, the autosomal recessive mutation in this particular gene results in defective zinc absorption, and consequently, the affected individuals manifest signs of zinc deficiency. Another mutation has been reported in mothers in SLC30A2 gene on chromosome 1p36.11 and results in decreased secretion of zinc into breast milk.[4][5]

Epidemiology

The prevalence of AE is 1 to 9:1,000,000, with a global incidence rate of 1:500,000 newborns. It appears among all groups, independent of ethnicity or sex. The disease usually manifests during infancy, during the time infants fed on breast milk are weaned, and earlier in infants who are formula-fed. Acquired zinc deficiency can manifest at any age.[5]

Pathophysiology

Zinc plays an important role in cellular processes, being an integral part of various metalloenzymes and transcription factors. It is particularly important in nucleic acid and protein synthesis, wound healing, normal immune function, and free-radical scavenging. As there is no free exchange of stored zinc, the metabolic needs must be met by the dietary supply of zinc. Human breast milk is a rich source of zinc, especially in the first 1 to 2 months of lactation, and there also is a zinc-binding ligand in breast milk which increases the bioavailability of zinc in human breast milk which is absent in animal milk.

Enteral zinc absorption occurs through the small intestine, primarily in the jejunum through the transporting protein ZIP4. Mutations in gene coding this protein prevent proper enteric zinc absorption, and the affected individuals manifest with features of zinc deficiency.[6]

Histopathology

The histology is typical but depends on the age of the lesion. Early lesions reveal a decrease in the granular layer with confluent parakeratosis. There is also an infiltrate of PMNs and mild spongiosis. With age, there is significant ballooning and reticular degeneration, with necrosis of keratinocytes. In the end stage of disease, one may see psoriasiform hyperplasia of the epidermis

History and Physical

The presentation is usually at the time of weaning in infants who are breastfed and earlier when they are formula-fed. In some cases, an infant who is breastfed may present with the manifestations of acrodermatitis enteropathica even before weaning. This could be due to the decreased secretion of zinc into breast milk due to a mutation in the mothers. The characteristic skin findings include sharply-demarcated, dry, scaly erythematous plaques that are usually periorificial on the face or the anogenital area. The upper lip usually is spared. The plaques can be psoriasiform, eczematous, vesiculobullous, pustular, or erosive with the characteristic crusted border in the periphery. Nail changes, including paronychia, may be present, and the hair becomes brittle, dry, and lusterless. In profound deficiency, diffuse alopecia may be seen. Angular cheilitis delayed wound healing and pigmentary abnormalities also have been reported.

The systemic features include diarrhea, irritability, lethargy, anorexia, growth retardation, anemia, amenorrhea, neuropsychiatric problems, perinatal morbidity, hypogonadism, hyposmia, and hypogeusia, and eye abnormalities including conjunctivitis, blepharitis, corneal opacities, and photophobia. Immunological abnormalities also are seen. Superinfection with Staphylococcus aureus and Candida albicans is reported. The classical triad of acrodermatitis enteropathica includes alopecia, diarrhea, and a periorificial and acral cutaneous rash. If untreated, the disease could be fatal. The differential diagnoses of AE include protein-energy malnutrition, psoriasis, seborrheic dermatitis, and glucagonoma syndrome. Acrodermatitis dysmetabolic is the term used for metabolic disorders that result in a clinical presentation resembling AE. The causes most often reported include acquired deficiencies of zinc, amino acids, or biotin.

Evaluation

The measurement of plasma zinc levels helps to confirm the diagnosis. A level of less than 70 microgram/L in fasting or less than 65 microgram/dL in non-fasting individuals is considered diagnostic. However, adequate care must be exercised while testing for zinc levels to obtain accurate values. The use of contaminated tubes, catheters, needles, or rubber stoppers may lead to erroneously high levels of zinc. The zinc levels may vary with the time of day, stress, or inflammation. The sample should be drawn in the morning using specially acid-washed glass bulbs or tubes. Low albumin levels may lead to a low zinc level; therefore, serum albumin also should be measured. Measurement of alkaline phosphatase, a zinc-dependent enzyme, also may be useful in some cases.

In cases where the diagnosis is doubtful, histopathological examination of the affected skin may be helpful but is not diagnostic. The characteristic changes include a psoriasiform hyperplasia with necrolysis, a term used for describing cytoplasmic pallor, confluent parakeratosis, spongiosis, and focal dyskeratosis.

Treatment / Management

The management of the disease usually involves enteral or parenteral supplementation of zinc. A lifelong supplementation with 3 mg/kg/day of elemental zinc may be required. Several formulations are available, and zinc sulfate is the preferred oral formulation. Four milligrams of zinc sulfate contains about 1 mg of elemental zinc. Zinc chloride is preferred for parenteral supplementation. The clinical response is often dramatic and occurs shortly after initiating treatment, usually within a few days. The first sign of response to treatment less irritability. Shortly after that, improvement in skin lesions is noted. While on therapy, regular monitoring of certain parameters is also required. This includes periodic measurement of zinc levels, complete blood counts, erythrocyte indices, serum copper level, and occult blood in the stool. Alkaline phosphate levels also may rise during treatment with zinc supplementation. High zinc levels in plasma may inhibit copper absorption due to competitive inhibition of a common cationic transporter; therefore, hypocupremia may result during therapy and should be monitored. Other adverse effects of zinc supplementation therapy could be gastric irritation and gastric hemorrhage.[7][8][9]

In cases of acquired zinc deficiency, the doses required for zinc supplementation are variable, depending on the underlying cause. Patients with malabsorption may need higher doses for response to treatment. Compresses and emollients applied at the affected areas may help in re-epithelialization when used along with zinc supplementation.

Complications

  • Infection
  • Gastric upset

Enhancing Healthcare Team Outcomes

Acrodermatitis enteropathica is a rare skin disorder associated with zinc deficiency. The primary caregiver and nurse practitioner must be aware of its presentation and refer the patient to the appropriate specialist to avoid the long-term morbidity. Patients treated with zinc have a 100% response, but without zinc, the disorder can lead to premature death. Pharmacist should assist the healthcare team in monitoring for complications. Untreated children will exhibit growth retardation, infections, and severe dermatitis.[10] (Level V)


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Acrodermatitis Enteropathica - Questions

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Which of the following is not true of acrodermatitis enteropathica?



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A 1-year-old patient presents with a history of refractory diarrhea, failure to thrive, irritability, dermatitis, and alopecia. Upon questioning, you determine that the infant was recently weaned from breastfeeding. Which of the following is most likely deficient?



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Deficiency of which of the following nutrients can result in acrodermatitis enteropathica?



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Which disease causes zinc deficiency?



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A 7-month infant is brought in with a progressive rash, irritability, and diarrhea. There is scaly, dry eczematous skin, erythematous patches, and crusty erosive pustular lesions. They are located around the mouth, on the cheeks, and on the hands and feet. Which of the following questions would be most important?



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Which of the following statement is not true about testing plasma zinc levels in acrodermatitis enteropathica?



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A 3-month-old formula-fed infant weighing 4 kg presented with irritability, diarrhea, and rashes on the face and genitalia. Examination revealed sharply marginated erythematous plaques with crusted borders on the periorificial area, buttocks, and medial thighs. The hair appeared brittle, dry, and lusterless. Which of the following need to be added in the daily treatment of this condition?



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A 7-year-old child with acrodermatitis enteropathica on oral zinc supplementation presents with pallor and low hemoglobin levels of 8 mg/dl. Peripheral smear reveals a microcytic hypochromic anemia. Iron supplementation was initiated but failed to be of benefit. Which of the following investigations may be most relevant in this condition?



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Acrodermatitis Enteropathica - References

References

Abu-Duhier F,Pooranachandran V,McDonagh AJG,Messenger AG,Cooper-Knock J,Bakri Y,Heath PR,Tazi-Ahnini R, Whole Genome Sequencing in an Acrodermatitis Enteropathica Family from the Middle East. Dermatology research and practice. 2018     [PubMed]
Wu D,Fung MA,Kiuru M,Sharon VR, Acquired bullous acrodermatitis enteropathica as a histologic mimic of pemphigus foliaceus in a patient on parenteral nutrition. Dermatology online journal. 2018 May 15     [PubMed]
Baruch D,Naga L,Driscoll M,Kao G, Acrodermatitis enteropathica from zinc-deficient total parenteral nutrition. Cutis. 2018 Jun     [PubMed]
Ogawa Y,Kinoshita M,Shimada S,Kawamura T, Zinc and Skin Disorders. Nutrients. 2018 Feb 11     [PubMed]
Ciampo IRLD,Sawamura R,Ciampo LAD,Fernandes MIM, ACRODERMATITIS ENTEROPATHICA: CLINICAL MANIFESTATIONS AND PEDIATRIC DIAGNOSIS. Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo. 2018 Apr-Jun     [PubMed]
Bin BH,Hojyo S,Seo J,Hara T,Takagishi T,Mishima K,Fukada T, The Role of the Slc39a Family of Zinc Transporters in Zinc Homeostasis in Skin. Nutrients. 2018 Feb 16     [PubMed]
Okhovat JP,O'Leary R,Hu M,Zussman J,Binder S,Worswick S, Acrodermatitis enteropathica in a patient with short bowel syndrome. Cutis. 2017 Nov     [PubMed]
Kelly S,Stelzer JW,Esplin N,Farooq A,Karasik O, Acquired Acrodermatitis Enteropathica: A Case Study. Cureus. 2017 Sep 8     [PubMed]
Dev T,Sethuraman G, Diagnosis of acrodermatitis enteropathica in resource limited settings. BMJ case reports. 2017 Aug 2     [PubMed]
Wang X,Zhou B, Dietary zinc absorption: A play of Zips and ZnTs in the gut. IUBMB life. 2010 Mar     [PubMed]

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