Zinc Deficiency


Article Author:
Luke Maxfield


Article Editor:
Jonathan Crane


Editors In Chief:
Ahmad Al Aboud
Jayakar Thomas
Pramod Nigam


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
3/18/2019 10:52:06 PM

Introduction

Zinc is an essential nutrient for humans and is extensively involved in protein, lipid, nucleic acid metabolism, and gene transcription. Its role within the human body is extensive in reproduction, immune function, wound repair, and on the microcellular level, macrophage, neutrophil, natural killer cell, and complement activity. Zinc is found in multiple food groups including meat, fish, legumes, and other dietary sources although absorption varies by substrate. Zinc deficiency can be inherited as absorption difficulties or can manifest from a decreased intake. Zinc deficiency is common worldwide, but mostly in developing countries. It presents with infectious, inflammatory, gastrointestinal, or cutaneous involvement. Treatment is largely through oral replacement usually resulting in quick clinical improvement.[1][2][3]

Etiology

Zinc is a divalent cation not synthesized within the human body and requires intake to maintain adequate levels. Deficiency can occur from decreased intake, inability to absorb the micronutrient, increased metabolic demand, or excessive loss.[4][5]

Endemic deficiency is common with up to one-third of the population in various parts of the world, primarily Southeast Asia and sub-Saharan Africa. Zinc deficiency is also prevalent in Iran, Egypt, and Turkey secondary to high phytate intake. Absorption occurs primarily in the distal duodenum and proximal jejunum while excretion is primarily gastrointestinal (GI) with some secretion through urine and sweat. Absorption is decreased with co-ingestion of phytates (found in legumes, nuts, seeds), calcium, and phosphate. Other causes of inadequate intake include Crohn’s disease and subsequent small bowel malabsorption, short bowel syndrome, hookworm infestation, pancreatic insufficiency, exclusive parental nutrition, strict vegetarian diets, and anorexia nervosa. Medications including penicillamine, various diuretics, and sodium valproate can inhibit absorption as well.

Acrodermatitis enteropathica illustrates inherited absorption deficiency. This is a rare disease with an incidence estimated at 1 per 500,000. It occurs as an autosomal recessive mutation of the SLC39A4 gene on chromosome 8q24.3 that encodes the Zip4 transporter.

Increased demand occurs in multiple settings, one of which is during pregnancy and lactation. Zinc requirements increase up to 2-fold during these times, and up to 2 mg per day of zinc loss occurs lasting up to 2 months postpartum. Additionally, preterm infants require higher zinc levels because of inadequate stores, decreased gut absorption, and higher metabolic rate.

Excess loss occurs by burns, hemodialysis, hemolysis, diarrhea, or urinary loss by alcohol use or diuretics. These lead to deficiency over a period of months. The body attempts to compensate for increased GI absorption by utilizing the small stores in skeletal muscle, bone, hair, liver, brain, and skin.

Epidemiology

It is estimated that up to 17% of the global population is at risk for inadequate zinc intake, while in South Asia up to 30% of the population may be deficient. Other areas at risk include sub-Saharan Africa and Central America. Notably, zinc intake worldwide correlates with growth stunting during child development in the first 5 years of life. Worldwide trends and prevalence of deficiency have largely been stable; however, notable reductions have been seen exemplified by China with a decrease of prevalence from 17% to 8% recorded in 2005.[6][7]

Pathophysiology

Zinc is a vital trace element. It plays multiple, indispensable roles within the human body. Zinc is involved in molecular synthesis including the formation of DNA, RNA, and proteins. It stabilizes ribosomes, cell membranes, and has protective effects by decreasing lipid peroxidation and subsequent free radicals. Beyond the molecular nuances of function, it is required for spermatogenesis, embryogenesis, and fetal growth.

Zinc has a significant role in the skin and is found in higher concentration in the epidermis than dermis with the majority found in the stratum spinosum. Tight regulation of intracellular zinc is maintained by transporters encoded by solute-linked carrier genes including Zinc transporter (ZnT; SLC30A). Other regulators include Zrt-Irt-like proteins ZIP; SLC39A). Within keratinocytes, zinc suppresses activation of tumor necrosis factor alpha and diminishes inducible nitric oxide synthase and nitric oxide production. Furthermore, chelation of intracellular zinc results in activation of caspase-3 and DNA fragmentation with resultant apoptosis of keratinocytes. The net effect is that zinc is required for normal keratinocyte proliferation and suppression of inflammation. Zip2 and Zip4 are present in keratinocytes facilitating appropriate proliferation and differentiation and are crucial in skin health. Zip10 is expressed in the outer root sheath of hair and is involved in hair growth and preservation.

Its role in immune function is also well described. Overall, it keeps the skin viable as an initial barrier to pathogens. It mediates innate immunity with the function of natural killer cells and neutrophils while influencing the acquired immune system through T-lymphocyte activation and regulation, Th1 cytokine production, B-lymphocyte function, and antibody production with subsequent immunoglobulin G formation. Macrophages utilize zinc for phagocytosis, intracellular killing, and cytokine production. Zinc potentiates programmed cell death through apoptosis.[8][9]

Histopathology

Punch biopsy of involved cutaneous lesions shows hyperplastic psoriasiform dermatitis with parakeratosis. The granular layer is often decreased or absent, and there may be palor of the upper epidermis. Cytoplasmic palor is a non-specific finding but may be the earliest change. It may also be absent in chronic lesions. The papillary dermis may show dilated tortuous vessels and demonstrate a mild perivascular mononuclear infiltrate. This finding is non-specific but suggestive of many vitamin deficiency dermatitis including B3 deficiency.

History and Physical

Risk factors and age of presentation will help to distinguish acquired versus inherited forms of zinc deficiency. Acquired forms will present with risk factors of inadequate supply, regional and geographic risk factors, excess loss, or increased demand as outlined above. The inherited disease presents earlier in life.

Regardless of inherited or acquired deficiency some signs and symptoms are similar although cutaneous involvement may be milder in the acquired subset. Zinc deficiency was first recognized as a cause of nutritional dwarfism in the Middle East. This was associated because of high phytate intake as described above. Multiple organ systems are affected by zinc deficiency. Its role within the reproductive system manifests clinically as hypogonadism and associated complications. Central nervous system (CNS) involvement can present as emotional lability, mental disturbances, as well as photophobia. Immune dysfunction predisposes individuals to a myriad of infectious complications. GI symptoms may manifest as significant diarrhea.

The cutaneous disease progresses over days and predominates on the periorificial location with angular cheilitis. Areas of friction such as elbows, knees, knuckles, malleolar areas, ankles, and the sacrum are often involved. Lesions are eczematous scaly plaques and maybe vesiculobullous or pustular. It is “scald like” and may fissure and may show some pathergy with areas of friction developing similar lesions. Annular psoriasiform plaques may have an overlying black crust and advancing margins with central scaling and lichenification. Nail involvement appears as paronychia, cuticle inflammation, Beau lines, of white transverse bands. Scalp involvement may first demonstrate thinning of hair, brittle spearhead appearance of hair or transverse striations with longitudinal splits or pseudo monilethrix.

Inherited deficiency as exemplified by acrodermatitis enteropathica is a rare inherited form of zinc malabsorption and often becomes symptomatic 4 to 6 weeks after an infant has stopped breastfeeding. Clinical symptoms include irritability, withdrawn disposition, growth impairment, anorexia, night blindness, pica, and photophobia. Cutaneous involvement includes the periorificial, gluteal, perineal, acral predominant burn-like psoriasiform lesions. Nail dystrophy and paronychia occur, and alopecia may develop. Delayed wound healing, conjunctivitis, and increased susceptibility to infection may also be clues.

Evaluation

Diagnosis can begin with establishing suspicion of inherited or acquired deficiency based on the above clinical features, and acquired disease can be suspected after evaluation of risk factors including geographical prevalence and age of presentation. [10][11]

Acrodermatitis enteropathica is suspected clinically and supported by laboratory findings and histopathology. Lab values will demonstrate low serum alkaline phosphatase (a zinc-dependent metalloenzyme) and low plasma zinc concentrations.

Serum studies and the ideal collection includes using zinc-free vacuum tubes, stainless steel needles, avoiding contact with rubber stoppers, avoiding hemolysis, separating plasma or serum from cells within 45 minutes, use of anticoagulants low in zinc concentration, as well as morning fasting samples optimize accuracy. Normal zinc levels are between 70 to 250 ug/dl in adults, and mild deficiency can manifest clinically when values decrease to 40 to 60 ug/dl. Urine zinc levels vary widely and are not a reliable marker for the acute state. Hair zinc level is also an unreliable marker in acute changes.

Punch biopsy and histopathology of affected tissue can support the diagnosis of necrolysis seen as cytoplasmic pallor, vacuolization, ballooning degeneration, and confluent necrosis of keratinocytes in the upper epidermis. Confluent parakeratosis is often present with loss of the granular layer and with dermal edema. An associated neutrophilic crust may be present. Individual keratinocytes often have pyknotic nuclei. These findings are non-specific and are often seen with pellagra and necrolytic migratory erythema. Late lesions of zinc deficiency may mimic psoriasis. Clinical improvement to zinc supplementation can also be confirmatory.

Treatment / Management

Treatment begins with oral replacement. Two to 3 mg/kg per day often cures all clinical manifestations within 1 to 2 weeks. Even in patients with acrodermatitis enteropathica, a disease of malabsorption, oral replacement with 1 to 2 mg/kg per day is still the standard of therapy with life-long supplementation. [12][13]

For preterm infants with zinc deficiency, normal breastfeeding is usually sufficient for correction, and the deficit usually resolves within weeks with no clinical symptoms. However, maternal breast milk can be zinc deficient if the mother's stores are depleted. Recommended daily dietary intake for lactating adult women increases from 11 mg per day to 12 mg per day. Also, low maternal secretion from the SLC30A2 mutation can occur. If breast secretion is low, the infant will need supplemental replacement.

Differential Diagnosis

Differential diagnosis includes multiple other nutritional deficiencies including biotin, vitamin B2 (riboflavin), or essential fatty acid deficiency.

Biotin deficiency can present with similar cutaneous findings but often additionally manifests with hypotonia, ataxia, seizures, and hearing loss. This deficiency is quantified with serum biotin estimation and increased urinary excretion of 3-hydroxyisovaleric acid. Riboflavin deficiency presents with ocular involvement and is confirmed with increased activity of the enzyme erythrocyte glutathione reductase. Clinically, it can appear similar to necrolytic migratory erythema, atopic dermatitis, psoriasis, and candidiasis. Necrolytic migratory erythema is related to glucagon secreting tumors, and this can be evaluated by serum glucagon levels above 1000 pg/ml.

Complications

Overcorrection with supplementation can occur and with very large doses can cause severe side effects including gastric irritation with nausea, vomiting, and gastric hemorrhage. Also, zinc intake competes with copper absorption, and over-treatment can lead to copper deficiency; therefore, copper levels may need to be monitored while replacing zinc.

Enhancing Healthcare Team Outcomes

Zinc deficiency is not common, but it occasionally occurs in people with restricted diets and malabsorption problems. Zinc deficiency can be prevented in the majority of cases by educating the public. The pharmacist, outpatient nurse, and dietitian play a vital role in educating the public about the foods that can be consumed to prevent zinc deficiency. In fact, the Federal government rules also suggest that the nutritional needs should be primarily met from foods and not by taking unnecessary supplements. Foods that are rich in zinc include vegetables, whole grains, low-fat dairy products, seafood, poultry, legumes, soy, and red meat. Also, the pharmacist should educate the patient on the potential interactions of medications with certain zinc supplements. Certain antibiotics, penicillamine, and diuretics can affect the absorption and excretion of zinc supplements. More important, the pharmacist should educate the patient about the health risks associated with excessive zinc intake. Through a multidisciplinary approach with a team of healthcare workers, one may be able to avoid zinc deficiency.[14][15] (Level V)

Outcomes

With treatment, there is often a rapid improvement of symptoms. Diarrhea may resolve within 24 hours, and skin lesions often heal within 1 to 2 weeks. Patients with inherited deficiencies should have zinc levels, and alkaline phosphatase should be monitored 3 to 6 months after initiation of replacement therapy and dose adjusted accordingly. [16][17](level V)


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Zinc Deficiency - Questions

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A patient presents with eczema, xerosis, seborrheic dermatitis, and alopecia. On physical exam, the patient has multiple oral ulcerations and a white coating on their tongue. Being an astute clinician, you suspect something doesn't look, smell, or taste right. What problem do you suspect?



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A 12-week-old who was born at 32 weeks gestation is brought in with perioral crusty plaques with distinct margins that are also on other parts of the face. The infant has been irritable and has diarrhea and areas of alopecia. Which of the following is the best treatment?



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A 72-year-old male undergoes a subtotal colectomy for a cecal volvulus. He is slow to recover and requires total parenteral nutrition for 3 weeks. After regaining bowel function, he experienced significant diarrhea. Now he is complaining of a lack of taste for food, hair loss, and a new perioral pustular rash. What is most likely deficient?



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A malnourished patient that has slow healing wounds and is developing alopecia should be evaluated for which one of the following deficiencies?



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While abroad in the Middle East you treat a 55-year-old male presenting at the behest of his wife. She states that he has been complaining of sensitivity to light, agitation, and new persistent diarrhea. You notice fissuring in the corners of his lips and an eczematous scaly rash on his knuckles. Complete blood count and complete metabolic panel are within normal limits. What is the most likely nutritional deficit?



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A 65-year-old Middle Eastern man who you recently started treatment for zinc deficiency returns and although skin lesions have resolved he describes new gait difficulties. Lab results reveal a B12 value well within normal limits, new anemia, and leukopenia. What complication is seen in this patient?



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A mother and father bring their eleven month old infant to the office. They say the infant, although initially amicable, has become unconsolable, often does not interact with the parents, has developed a gluteal scaly rash, and they think the baby has stopped growing. History also revealed that the mother had stopped breastfeeding 5 weeks ago and was feeding the infant exclusively with a new fad homemade formula. What is the most cause of this child's constellation of symptoms?



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Zinc Deficiency - References

References

McClung JP, Iron, Zinc, and Physical Performance. Biological trace element research. 2018 Aug 15     [PubMed]
Fritz J,Walia C,Elkadri A,Pipkorn R,Dunn RK,Sieracki R,Goday PS,Cabrera JM, A Systematic Review of Micronutrient Deficiencies in Pediatric Inflammatory Bowel Disease. Inflammatory bowel diseases. 2018 Aug 21     [PubMed]
Fallah A,Mohammad-Hasani A,Colagar AH, Zinc is an Essential Element for Male Fertility: A Review of Zn Roles in Men's Health, Germination, Sperm Quality, and Fertilization. Journal of reproduction     [PubMed]
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Han YM,Yoon H,Lim S,Sung MK,Shin CM,Park YS,Kim N,Lee DH,Kim JS, Risk Factors for Vitamin D, Zinc, and Selenium Deficiencies in Korean Patients with Inflammatory Bowel Disease. Gut and liver. 2017 May 15     [PubMed]
Hess SY, National Risk of Zinc Deficiency as Estimated by National Surveys. Food and nutrition bulletin. 2017 Mar     [PubMed]
Parrott J,Frank L,Rabena R,Craggs-Dino L,Isom KA,Greiman L, American Society for Metabolic and Bariatric Surgery Integrated Health Nutritional Guidelines for the Surgical Weight Loss Patient 2016 Update: Micronutrients. Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2017 May     [PubMed]
Freitas BA,Lima LM,Moreira ME,Priore SE,Henriques BD,Carlos CF,Sabino JS,Franceschini Sdo C, Micronutrient supplementation adherence and influence on the prevalences of anemia and iron, zinc and vitamin A deficiencies in preemies with a corrected age of six months. Clinics (Sao Paulo, Brazil). 2016 Aug     [PubMed]
Santos CA,Fonseca J,Lopes MT,Carolino E,Guerreiro AS, Serum zinc evolution in dysphagic patients that underwent endoscopic gastrostomy for long term enteral feeding. Asia Pacific journal of clinical nutrition. 2017 Mar     [PubMed]
Ernst B,Thurnheer M,Schmid SM,Schultes B, Evidence for the necessity to systematically assess micronutrient status prior to bariatric surgery. Obesity surgery. 2009 Jan     [PubMed]
Narváez-Caicedo C,Moreano G,Sandoval BA,Jara-Palacios MÁ, Zinc Deficiency among Lactating Mothers from a Peri-Urban Community of the Ecuadorian Andean Region: An Initial Approach to the Need of Zinc Supplementation. Nutrients. 2018 Jul 5     [PubMed]
Dao DT,Anez-Bustillos L,Cho BS,Li Z,Puder M,Gura KM, Assessment of Micronutrient Status in Critically Ill Children: Challenges and Opportunities. Nutrients. 2017 Oct 28     [PubMed]

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