Acrodermatitis enteropathica

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acrodermatitis enteropathica

Acrodermatitis enteropathica

Acrodermatitis enteropathica is also called acrodermatitis enteropathy, primary zinc malabsorption syndrome, congenital zinc deficiency, Danbolt-Closs syndrome or Brandt syndrome, is a rare inherited form of zinc deficiency that is characterized by the triad of dermatitis (well-demarcated redness and crusting around the mouth and/or anus [peri-acral and periorificial dermatitis]), diarrhea, and hair loss (alopecia) 1, 2, 3, 4, 5, 6, 7. On the other hand, secondary or acquired zinc deficiency is known as acquired acrodermatitis enteropathica or acrodermatitis enteropathica-like condition. Paronychia (bacterial nail infection where the infected area can become swollen, red, and painful, and a pus-filled blister or abscess may form), onychodystrophy (nail disorders that may manifest as a misshapen, damaged, infected or discolored nail), angular stomatitis (inflammation and small cracks in one or both corners of the mouth), cheilitis, conjunctivitis (pink eye or inflammation or infection of the outer membrane of the eyeball and the inner eyelid) and photophobia (abnormal sensitivity to light, especially of the eyes) can also occur in acrodermatitis enteropathica 8, 9. An individual with acrodermatitis enteropathica progresses with difficulties regarding: weight gain, delayed growth, neuro-psychic disorders, delayed puberty, male hypogonadism, anemia, anorexia, reduced ability to taste things (hypogeusia) and difficulty to heal wounds 10. Furthermore, zinc deficiency changes immunity, contributing with the high predisposition to fungal and bacterial infection, which can trigger severe sepsis, and with the high mortality rates in developing countries 11, 12.

Acrodermatitis enteropathica is an autosomal recessive condition caused by a mutation in the SLC39A4 gene on the chromosome band 8q24.3, that codes the zinc transporter protein, ZIP4 (zinc or iron-regulated transporter-like protein), which is expressed in the duodenum and jejunum, and its mutation reduces the duodenum and jejunum ability to absorb dietary zinc 1, 4, 13, 14, 15, 16, 17, 18, 19.

Zinc is a very important micronutrient of the diet, a component of more than two-hundred metalloenzymes that are involved in many cellular processes throughout the body and essential for the proper functioning of the various metabolic and biochemical pathways of the body. These include the production of anti-inflammatory agents (cytokines and antioxidants) and the normal functioning of the brain. Zinc in human milk is more absorbable than that from infant formulas or cow’s milk, hence acrodermatitis enteropathica may be diagnosed later in breast-fed babies compared to formula-fed babies. Zinc is also found in meat, shellfish and wheat germ. Foods of plant origin are mostly low in zinc. Phytates present in cereals and soy, and high levels of calcium, can reduce the absorption of zinc through the duodenum.

Acrodermatitis enteropathica results from mutations in the zinc transporter gene SLC39A4 (solute carrier family 39 member A4), leading to improper enteral zinc absorption. Acrodermatitis enteropathica was first described by Brandt in 1936 and later identified as a distinct disease by Danbolt and Closs 5, 6, 7, 1. Zinc deficiency acquired secondary to malabsorption syndromes, liver or kidney disease, dietary habits, and iatrogenic causes also can present with clinical features simulating acrodermatitis enteropathica 20.

The prevalence of acrodermatitis enteropathica is 1 to 9:1,000,000, with a global incidence rate of 1:500,000 newborns 21. 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 22.

The gold standard for the diagnosis of acrodermatitis enteropathica is plasma zinc deficiency; however, acrodermatitis enteropathica may present with serum zinc concentrations within normal reference range, even when there is tissue zinc depletion. Therefore, the dosage of alkaline phosphatase (ALP) can be useful. Since alkaline phosphatase (ALP) is a zinc-dependent enzyme, it responds to zinc replacement by increasing the low serum alkaline phosphatase (ALP) levels observed initially 23.

Treatment for acrodermatitis enteropathica is lifelong supplementation with elemental zinc (3 mg per kg per day); a higher dosage is needed to overcome the zinc transporter defect 10. The only known adverse effect of zinc supplementation is copper deficiency. High zinc levels inhibit copper absorption by competitively inhibiting a common cationic transporter; therefore, copper levels should be monitored during treatment of zinc deficiency.

Untreated patients with inherited acrodermatitis enteropathica usually die in the first few years of life 24, 25. Untreated infants exhibit severe growth retardation, dermatitis, alopecia, secondary bacterial and fungal infections, and neurologic and behavioral changes. However, all symptoms are reversible with zinc therapy 24, 25. Patients with acrodermatitis enteropathica uniformly respond to zinc therapy with a 100% survival rate. With zinc supplementation, various symptoms completely resolve or substantially improve.

Figure 1. Acrodermatitis enteropathica (before zinc supplementation)

acrodermatitis enteropathica

Footnote: Acrodermatitis enteropathica before treatment (a) Mouth & face. (b) The perianal area has erythema with yellow-black sputum. (c & d) The blisters are visible on both hands and feet

[Source 26  ]

Figure 2. Acrodermatitis enteropathica (after zinc supplementation)

Acrodermatitis enteropathica after zinc supplementation

Footnote: Acrodermatitis enteropathica after 1 year of zinc supplementation: (a) Face. (b) Perineum. (c) Hands. (d) Feet

[Source 26  ]

What is the role of zinc in the body?

Zinc is an essential mineral that is naturally present in some foods, added to others, and available as a dietary supplement. Zinc is also found in many cold lozenges and some over-the-counter drugs sold as cold remedies. Zinc is a nutrient that people need to stay healthy. A daily intake of zinc is required to maintain a steady state because the body has no specialized zinc storage system 27. Absorption of zinc occurs in the jejunum of the small intestine 28.

Zinc is found in cells throughout the body, found mainly in bones, teeth, hair, skin, liver, muscle, leukocytes, and testes 29. Zinc plays an important role in a variety of cellular processes, including protein synthesis, wound healing, and immune function 30. Zinc helps the immune system fight off invading bacteria and viruses. The body also needs zinc to make proteins and DNA, the genetic material in all cells. During pregnancy, infancy, and childhood, the body needs zinc to grow and develop properly. Zinc also helps wounds heal and is important for proper senses of taste and smell.

Animal proteins are a good source of zinc. Beef, pork, and lamb contain more zinc than fish. The dark meat of a chicken has more zinc than the light meat. Other good sources of zinc are nuts, whole grains, legumes, and yeast.

Dietary sources of zinc include human breast milk, meat, shellfish, chickpeas, cashews, and pumpkin seeds.

Fruits and vegetables are not good sources, because the zinc in plant foods is not as available for use by the body as the zinc from animal sources. Therefore, low-protein diets and vegetarian diets tend to be low in zinc.

Zinc key points

  • Zinc is a nutritionally essential mineral needed for catalytic, structural, and regulatory functions in the body.
  • Severe zinc deficiency is rare and caused by an inherited condition called acrodermatitis enteropathica. Acquired zinc deficiency is primarily due to malabsorption syndromes and chronic alcoholism.
  • Dietary zinc deficiency is quite common in the developing world, affecting an estimated 2 billion people. Consumption of diets high in phytate and lacking foods from animal origin drive zinc deficiency in these populations.
  • The recommended dietary allowance (RDA) for adult men and women is 11 mg/day and 8 mg/day of zinc, respectively.
  • Long-term consumption of zinc in excess of the tolerable upper intake level (UL) is 40 mg/day for adults can result in copper deficiency 31. Copper deficiency has also been reported following chronic use of excessive amounts of zinc-containing denture creams (≥2 tubes per week containing 17-34 mg/g of zinc) 32.
  • Dietary zinc deficiency has been associated with impaired growth and development in children, pregnancy complications, and immune dysfunction with increased susceptibility to infections.
  • Supplementation with doses of zinc in excess of the upper intake level (40 mg/day for adults) is effective to reduce the duration of common cold symptoms.
  • Milder gastrointestinal distress has been reported at doses of 50 to 150 mg/day of supplemental zinc. Single doses of 225 to 450 mg of zinc usually induce vomiting.
  • Current evidence suggests that supplemental zinc may be useful in the management of chronic conditions, such as age-related macular degeneration, diabetes mellitus, Wilson’s disease, and HIV/AIDS.
  • Zinc bioavailability is relatively high in meat, eggs, and seafood; zinc is less bioavailable from whole grains and legumes due to their high content in phytate that inhibits zinc absorption.

Most Americans get enough zinc from the foods they eat.

However, certain groups of people are more likely than others to have trouble getting enough zinc:

  • People who have had gastrointestinal surgery, such as weight loss surgery, or who have digestive disorders, such as ulcerative colitis or Crohn’s disease. These conditions can both decrease the amount of zinc that the body absorbs and increase the amount lost in the urine.
  • Vegetarians or vegans because they do not eat meat, which is a good source of zinc. Also, the beans and grains they typically eat have compounds that keep zinc from being fully absorbed by the body. For this reason, vegetarians might need to eat as much as 50% more zinc than the recommended amounts.
  • Women who are pregnant or breastfeeding because they need more zinc for their growing baby and to make breast milk.
  • Older infants who are breastfed because breast milk does not have enough zinc for infants over 6 months of age. Older infants who do not take formula should be given foods that have zinc such as pureed meats. Formula-fed infants get enough zinc from infant formula.
  • Alcoholics because alcoholic beverages decrease the amount of zinc that the body absorbs and increase the amount lost in the urine. Also, many alcoholics eat a limited amount and variety of food, so they may not get enough zinc.
  • Children and individuals who have sickle cell disease, possibly because the medications they take can cause low levels of zinc. These people might benefit from taking zinc supplements.

Can too much zinc be harmful?

Yes, if you get too much. Signs of too much zinc include nausea, vomiting, dizziness, headaches, gastric distress, loss of appetite, stomach cramps and diarrhea 33, 34. When people take too much zinc for a long time, at doses of 50 mg zinc or more—typically from supplements or excessive use of denture adhesive creams that contain zinc, they sometimes have problems such as low copper levels, lower immunity, and low levels of HDL cholesterol (the “good” cholesterol) 33, 34, 35. According to a few reports, overuse of denture adhesive creams containing up to 34 mg zinc per gram of product can lead to neurological symptoms (including sensory ataxia and myelopathy) and anemia. Zinc-free formulations are available to prevent these effects 33, 32, 36.

One case report cited severe nausea and vomiting within 30 minutes of ingesting 4 g of zinc gluconate (570 mg elemental zinc) 37. Intakes of 150–450 mg of zinc per day have been associated with such chronic effects as low copper status, altered iron function, reduced immune function, and reduced levels of high-density lipoproteins 38. Reductions in a copper-containing enzyme, a marker of copper status, have been reported with even moderately high zinc intakes of approximately 60 mg/day for up to 10 weeks 39. The doses of zinc used in the AREDS study (80 mg per day of zinc in the form of zinc oxide for 6.3 years, on average) have been associated with a significant increase in hospitalizations for genitourinary causes, raising the possibility that chronically high intakes of zinc adversely affect some aspects of urinary physiology 40. Very high doses of zinc from supplements (142 mg/day) might also interfere with magnesium absorption and disrupt magnesium balance 41.

The amount of zinc obtained from food is rarely as high as 50 mg, so the zinc in foods is unlikely to cause zinc toxicity 42.

In order to prevent copper deficiency, the US Food and Nutrition Board set the tolerable upper intake level (UL) for zinc from foods, beverages, supplements, and medications for healthy adults at 40 mg/day 31. Table 1 below lists the tolerable upper intake levels (ULs) for zinc from foods, beverages, supplements, and medications for healthy adults by age group. The tolerable upper intake levels (ULs) do not apply to individuals receiving zinc for medical treatment, but such individuals should be under the care of a physician.

Table 1. Tolerable Upper Intake Levels (ULs) for Zinc

AgeMaleFemalePregnancyLactation
Birth to 6 months4 mg4 mg
7–12 months5 mg5 mg
1–3 years7 mg7 mg
4–8 years12 mg12 mg
9–13 years23 mg23 mg
14–18 years34 mg34 mg34 mg34 mg
19+ years40 mg40 mg40 mg40 mg
[Source 42 ]

Acrodermatitis enteropathica cause

Primary acrodermatitis enteropathica or congenital form of acrodermatitis enteropathica is due to malabsorption of zinc through the intestinal cells. Primary acrodermatitis enteropathica is associated with mutations in a gene SLC39A4 on chromosome 8q24.3 that codes the zinc transporter protein, ZIP4 (zinc or iron-regulated transporter-like protein) and is transmitted as an autosomal recessive genetic disorder 43. It is thought that the missing protein may be responsible for decreased zinc uptake and abnormal zinc metabolism. ZIP 4 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 in the duodenum and jejunum, and consequently, the affected individuals manifest signs of zinc deficiency 44.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. To have inherited acrodermatitis enteropathica you must inherit two defective genes (one from each parent) i.e. the inheritance is autosomal recessive. If an individual receives one normal gene and one defective gene, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Some women fail to generate adequate zinc levels in their breast milk and that can also have a genetic cause. A second genetic cause of acrodermatitis enteropathica has been reported in breastfeeding mothers due to SLC30A2 gene on chromosome 1p36.11 that encodes a zinc transporter, ZnT2, and results in decreased secretion of zinc into breast milk 45, 46. In a nursing mother, this effectively decreases the zinc transfer from serum to breast milk, producing a transient zinc deficiency in an exclusively breastfed child 47. This SLC30A2 gene mutation does not require two gene abnormalities, one is sufficient and people who have this condition have a 50% chance of passing it on to their offspring.

Acrodermatitis enteropathica has been reported as a presentation of food allergy. Serum total immunoglobulin E (IgE) and food-specific IgE levels to milk, soybean, wheat, and peanut have been measured to evaluate for food allergy. Undiagnosed food allergy can lead to profound zinc deficiency. Food allergy should be suspected in children with clinical symptoms of acquired acrodermatitis enteropathica 48.

Transient, symptomatic zinc deficiency has been reported in breastfed, low-birthweight, premature infants and should be considered a rare but important disorder hallmarked by periorificial and acral dermatitis, with symptoms disappearing when nursing ends 49. These reports illustrate the importance of zinc in rapidly growing preterm infants.

Genetic counseling is recommended for families of patients with the congenital form of acrodermatitis enteropathica.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

What is an acrodermatitis enteropathica-like condition?

An acrodermatitis enteropathica-like condition presents with similar features to acrodermatitis enteropathica (inherited form of zinc deficiency), but is caused by acquired zinc deficiency or a disorder of amino acid or fatty acid metabolism 4. An acrodermatitis enteropathica-like condition can be categorized as secondary to acquired zinc deficiency or to a metabolic disorder unrelated to zinc deficiency 4.

When an acrodermatitis enteropathica-like condition is related to acquired zinc deficiency, the lack of zinc leads to abnormal keratinization, cell proliferation, and defective immune response 4. In metabolic disorders, amino acid or fatty acid deficiency leads to reduced keratinocyte growth and differentiation 4.

Acrodermatitis enteropathica-like conditions include:

  • Acrodermatitis metabolica when secondary to a metabolic disorder
  • Acrodermatitis acidemica when secondary to an organic acidemia 4.

Acquired zinc deficiency

Causes of acquired zinc deficiency include 4, 13, 50, 51:

  • Inadequate zinc intake (due to low breast milk levels, anorexia nervosa, total parenteral nutrition, or inadequate diet)
  • Intestinal malabsorption (celiac disease, Crohn disease, ulcerative colitis, cystic fibrosis, pancreatic disease, pancreatic dysfunction, intestinal bypass surgery, high copper/iron/phytate intake, short bowel syndrome, medications)
  • Increased urinary zinc excretion or excessive urinary loss of zinc (nephrotic syndrome, liver cirrhosis, infection, diabetes mellitus, excessive alcohol ingestion, diuretics)
  • Increased digestive fluid loss (intestinal fistula, diarrhea)
  • Increased requirements (pregnancy, lactating mothers, preterm infants)
  • Low albumin and high metabolic demands (thermal burn, trauma, excessive sweating, liver cirrhosis, extensive surgery, hemolysis).
  • Necrolytic migratory erythema can present with a rash similar to acrodermatitis enteropathica in adults and is associated with glucagonoma 4. The necrolytic migratory erythema skin lesions resolve if the glucagonoma tumor is removed 52, 53, 54.

Metabolic disorders

An acrodermatitis enteropathica-like condition related to a metabolic disorder can be secondary to:

  • A congenital condition present in the newborn period
  • An acquired deficiency of protein or biotin deficiency, which can present at various stages of life 4, 50.

Acrodermatitis enteropathica-like conditions secondary to metabolic disorders are caused by abnormalities disrupting the metabolism of amino acids or fatty acids 4. This can be direct, through disruption of the urea cycle, or by affecting co-factors, notably biotin 4, 13, 50.

Metabolic disorders responsible for acrodermatitis enteropathica-like conditions include 4, 13, 50:

  • Organic acidemias, including:
    • Propionic acidemia
    • Methylmalonic acidemia
    • Glutaric aciduria type 1
    • Multiple carboxylase deficiency
  • Maple syrup urine disease
  • Phenylketonuria (PKU)
  • Ornithine transcarbamylase deficiency
  • Citrullinaemia
  • Carbamoyl phosphate synthetase deficiency
  • Kwashiorkor (protein-energy malnutrition)
  • Acquired biotin deficiency due to a restrictive diet (rare).

Acrodermatitis enteropathica symptoms

Zinc is an essential coenzyme in metalloenzymes, including alkaline phosphatase; this enzyme regulates gene expression and is an important structural component of gene regulatory proteins, such as those required for intracellular binding of tyrosine kinases to T cell receptors 45. Zinc can promote growth, sexual organ development and wound healing and has repairing effects on oral mucosa, hair, nails and other body parts 55. Zinc deficiency can present in various clinical symptoms, such as growth retardation, decreased immune function and different skin or gastrointestinal injuries 56.

Hereditary acrodermatitis enteropathica is characterized by periorificial dermatitis, alopecia and diarrhea. These three symptoms simultaneously occur in only 20% of patients 57. Symptoms of primary acrodermatitis enteropathica usually occur in bottle-fed infants within a few days or weeks after birth and breast-fed infants soon after weaning. Both males and females are equally affected. Acquired acrodermatitis enteropathica can occur at any age, but is mostly diagnosed in older adults. Advanced acrodermatitis enteropathica symptoms may include neuropsychiatric disorders, hypogonadism, growth retardation and immune system dysfunction.

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 acrodermatitis enteropathica 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 acrodermatitis enteropathica. The causes most often reported include acquired deficiencies of zinc, amino acids, or biotin.

Skin findings in both types of acrodermatitis enteropathica are characteristic.

  • Red and inflamed patches of dry and scaly skin arise around body openings such as the mouth, anus, and eyes, and the skin on elbows, knees, hands, and feet. The rash may look like atopic dermatitis.
  • Patches evolve into crusted, blistered, pus-filled and eroded lesions.
  • There is usually a sharp demarcation between the affected area and normal skin.
  • Skin around the nails becomes inflamed (paronychia) and there may be nail ridging.
  • Diffuse hair loss on the scalp, eyebrows and, eyelashes may be reported.
  • Lesions may develop secondary infection with Candida albicans or Staphylococcus aureus.
  • Mucosal features include red glossy tongue, angular cheilitis and mouth ulcers.
  • Wound healing is impaired.

Noncutaneous symptoms

Other features of acrodermatitis enteropathica include:

  • Conjunctivitis
  • Sensitivity to light
  • Loss of appetite
  • Diarrhea, mild or severe
  • Irritability (babies cry and whine incessantly)
  • Depressed mood
  • Growth failure.

Acrodermatitis enteropathica complications

If untreated, the lesions of acrodermatitis enteropathica may become secondarily infected with Staphylococcus aureus and Candida albicans. Additionally, untreated patients with acrodermatitis enteropathica may eventually lead to multiple organ failure and death 26. Zinc deficiency accounts for 4% of morbidity and mortality in children aged from 6 months to 5 years worldwide 58.

High-dose zinc supplementation occasionally causes gastric upset and can adversely affect copper metabolism 59.

Acrodermatitis enteropathica diagnosis

The gold standard for the diagnosis of acrodermatitis enteropathica is serum or plasma zinc deficiency; however, acrodermatitis enteropathica may present with serum zinc concentrations within normal reference range, even when there is tissue zinc depletion. Therefore, the dosage of alkaline phosphatase (ALP) can be useful. Since alkaline phosphatase (ALP) is a zinc-dependent enzyme, it responds to zinc replacement by increasing the low serum alkaline phosphatase (ALP) levels observed initially 23.

Acquired zinc deficiency is associated with low serum zinc levels and alkaline phosphatase (ALP) 13. Zinc levels and alkaline phosphatase (ALP) tend to be normal in acrodermatitis enteropathica-like conditions related to metabolic disorders 4.

In healthy people, the amount of zinc in serum or plasma is 80 to 120 microgram (mcg)/dL (12 to 18 micromol/L) 33. Serum zinc levels below 70 mcg/dL in women and 74 mcg/dL in men indicate zinc deficiency 42.

If zinc deficiency and acrodermatitis enteropathica are clinically suspected, the following investigations may be helpful.

  • Serum or plasma zinc levels to confirm the diagnosis (normal levels are 10.7–23.0 micromol/L).
  • Urinary zinc excretion may be reduced.
  • Blood count may reveal anemia.
  • Skin biopsy may show characteristic features.

The measurement of plasma zinc levels helps to confirm the diagnosis. A level of less than 70 microgram/dL 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. Zinc concentrations in serum are associated with the patient’s sex and age as well as the time of the blood draw (morning vs. evening) and do not always correlate with dietary or supplemental zinc intakes 60. Zinc levels also fluctuate in response to other factors, including infections, changes in steroid hormones, stress and muscle catabolism during weight loss or illness 61, 62, 31, 34.

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.

Doctors consider risk factors (such as inadequate caloric intake, chronic alcohol use, and malabsorptive digestive diseases) and signs of zinc deficiency (such as impaired growth in infants and children) when they assess a patient’s zinc status 31.

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.

A full blood count may reveal cytopenias in both acquired zinc deficiency and metabolic disorders 13, 63.

The initial blood tests for an organic acidemia may include 63:

  • pH
  • The partial pressure of carbon dioxide
  • Bicarbonate
  • Lactate
  • Electrolytes
  • Urea
  • Creatinine
  • Glucose
  • Pyruvate
  • Ammonia.

Levels of specific amino acids or enzyme activity and the presence of organic acids in the urine may support a specific diagnosis 4, 63.

Newborn screening detects many of the congenital metabolic causes of acrodermatitis enteropathica-like conditions and is available in many parts of the world including Australia, the United Kingdom, the United States, and Canada 63.

A skin biopsy of an acrodermatitis enteropathica-like condition has non-specific histopathology; epidermal pallor and confluent parakeratosis may be observed 64.

Acrodermatitis enteropathica differential diagnosis

Acrodermatitis enteropathica differential diagnosis may include 65, 66, 67, 68), 69), 13, 51, 61, 50, 70:

  • Atopic eczema or atopic dermatitis— this typically spares the napkin area, does not result in hair loss, and usually presents after early infancy
  • Psoriasis — this involves groin flexures (napkin psoriasis) with typical plaques elsewhere
  • Seborrheic dermatitis — this has a typical flexural distribution
  • Necrolytic migratory erythema — this is an exfoliative periorificial dermatitis seen in infants with metabolic disorders such as biotinidase deficiency, and urea cycle, organic acid and essential fatty acid disorders (often included in routine neonatal metabolic screening)
  • Pellagra — due to niacin deficiency — and pellagra-like dermatitis in Hartnup disease
  • Bullous disorders — particularly epidermolysis bullosa (EB) and linear IgA bullous disease
  • Langerhans cell histiocytosis — this can present with a haemorrhagic papulopustular rash in the napkin area
  • Candida superinfection
  • Thermal burn — this should raise suspicion of non-accidental injury
  • Napkin dermatitis — this is confined to the napkin area and has no systemic features.

Acrodermatitis enteropathica treatment

The inherited form of acrodermatitis enteropathica was usually fatal until the role of zinc was discovered in 1973. Acrodermatitis enteropathica is treated with 1 to 3 mg/kg body weight of oral zinc supplementation per day for life 10. Several formulations are available, and zinc sulfate is the preferred oral formulation. Zinc gluconate is better tolerated than zinc sulfate. 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 71. Although zinc is usually non-toxic, high doses for a long period can result in gastrointestinal symptoms, dizziness and copper deficiency, leading to anemia.

In cases of acquired acrodermatitis enteropathica, the doses required for zinc supplementation are variable, depending on the underlying cause. Patients with malabsorption may need higher doses for response to treatment.

  • An acrodermatitis enteropathica-like condition secondary to acquired zinc deficiency will resolve after oral zinc supplementation, usually at an initial dose of 0.5–1 mg/kg/day of elemental zinc 13. Whether there is an ongoing need for zinc replacement will depend on the cause 13, 72.
  • An acrodermatitis enteropathica-like condition secondary to a metabolic disorder generally responds to dietary manipulation and medication in the form of specific organic supplements to correct metabolic deficiencies 73. Expert assistance should be sought from a nutritionist.

Compresses and emollients applied at the affected areas may help in re-epithelialization when used along with zinc supplementation.

Zinc can be given during pregnancy. Acrodermatitis enteropathica exacerbation during pregnancy or the stress of disease may require an increase in zinc therapy 74.

After zinc replacement, the skin lesions heal within one to two weeks, diarrhea ceases, and irritability and depression of mood improve within 24 hours.

Warm compresses to remove the scale crust, followed by application of white petrolatum to eroded skin lesions, may enhance reepithelialization when used concurrently with zinc replacement.

Secondary bacterial and/or fungal infection of lesions require appropriate antibiotic therapy.

Acrodermatitis enteropathica Diet

Although no special diet is required for acrodermatitis enteropathica patients, as long as zinc supplementation is continued, certain foods contain increased levels of zinc, including oysters, crab, beef, pork, and fowl. Zinc content is directly related to protein content 75.

You can get recommended amounts of zinc by eating a variety of foods including the following:

  • Oysters, which are the best source of zinc. Oysters contain more zinc per serving than any other food.
  • Red meat, poultry, seafood such as crab and lobsters, and fortified breakfast cereals, which are also good sources of zinc. They provide the majority of zinc in the American diet.
  • Beans, nuts, whole grains, and dairy products, which provide some zinc.

Animal proteins are a good source of zinc. Beef, pork, and lamb contain more zinc than fish. The dark meat of a chicken has more zinc than the light meat. Other good sources of zinc are nuts, whole grains, legumes, and yeast.

Fruits and vegetables are not good sources, because the zinc in plant foods is not as available for use by the body as the zinc from animal sources. Therefore, low-protein diets and vegetarian diets tend to be low in zinc.

Phytates (is the principal storage form of phosphorus in many plant tissues, especially bran and seeds), which are present in whole-grain breads, cereals, legumes, and other foods—bind zinc and inhibit its absorption 39, 76, 77. Therefore, the bioavailability of zinc from grains and plant foods is lower than that from animal foods, although many grain- and plant-based foods are still good sources of zinc 39.

Although breast milk typically provides adequate concentrations of zinc for full-term infants, it may be insufficient for preterm infants given their relatively increased metabolic rate and limited liver zinc storage from the third trimester of pregnancy 78, 79.

The U.S. Department of Agriculture’s (USDA’s) Nutrient Database website (https://fdc.nal.usda.gov) lists the nutrient content of many foods and provides a comprehensive list of foods containing zinc arranged by nutrient content (https://ods.od.nih.gov/pubs/usdandb/Zinc-Content.pdf) and by food name (https://ods.od.nih.gov/pubs/usdandb/Zinc-Food.pdf).

Table 2. Food Sources of Zinc

FoodMilligrams (mg)
per serving		Percent DV*
Oysters, cooked, breaded and fried, 3 ounces74.0493
Beef chuck roast, braised, 3 ounces7.047
Crab, Alaska king, cooked, 3 ounces6.543
Beef patty, broiled, 3 ounces5.335
Breakfast cereal, fortified with 25% of the DV for zinc, ¾ cup serving3.825
Lobster, cooked, 3 ounces3.423
Pork chop, loin, cooked, 3 ounces2.919
Baked beans, canned, plain or vegetarian, ½ cup2.919
Chicken, dark meat, cooked, 3 ounces2.416
Yogurt, fruit, low fat, 8 ounces1.711
Cashews, dry roasted, 1 ounce1.611
Chickpeas, cooked, ½ cup1.39
Cheese, Swiss, 1 ounce1.28
Oatmeal, instant, plain, prepared with water, 1 packet1.17
Milk, low-fat or non fat, 1 cup1.07
Almonds, dry roasted, 1 ounce0.96
Kidney beans, cooked, ½ cup0.96
Chicken breast, roasted, skin removed, ½ breast0.96
Cheese, cheddar or mozzarella, 1 ounce0.96
Peas, green, frozen, cooked, ½ cup0.53
Flounder or sole, cooked, 3 ounces0.32

Footnote: * DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration to help consumers compare the nutrient contents of products within the context of a total diet. The DV for zinc is 15 mg for adults and children age 4 and older. Food labels, however, are not required to list zinc content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

[Source 80]

Acrodermatitis enteropathica prognosis

The prognosis of acrodermatitis enteropathica is generally good with prompt diagnosis and zinc replacement but can be potentially fatal without treatment. With zinc supplementation, the response rate is 100%; however, without appropriate zinc supplementation, acrodermatitis enteropathica usually is lethal within the first few years of life. Untreated infants exhibit severe growth retardation, dermatitis, alopecia, secondary bacterial and fungal infections, and neurologic and behavioral changes; however, all symptoms are reversible with therapy.

An acrodermatitis enteropathica-like condition secondary to acquired zinc deficiency has a favourable prognosis if identified early 72, 61. The skin, gastrointestinal, and psychological manifestations tend to resolve within days to weeks following zinc replacement 61.

An acrodermatitis enteropathica-like condition secondary to a metabolic disorder can have a high mortality rate in the newborn period if undiagnosed. This is reduced to some extent by detection in the newborn period with the help of screening programmes 73. A significant number of children diagnosed early with congenital metabolic disorders will still have ongoing problems with metabolic crises and neurocognitive development 73, 81.

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