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Invited Review

Nutrition in Clinical Practice

Volume 34 Number 4
Hair, Nails, and Skin: Differentiating Cutaneous August 2019 490–503
C 2019 American Society for

Manifestations of Micronutrient Deciency Parenteral and Enteral Nutrition
DOI: 10.1002/ncp.10321

Michelle DiBaise, DHSc, PA-C, DFAAPA 1 ; and Sherry M. Tarleton,



Printed by [Wiley Online Library - - /doi/epdf/10.1002/ncp.10321] at [24/01/2021].

Micronutrient deciencies (MNDs) commonly lead to cutaneous abnormalities involving the skin, hair, and nails, and these
cutaneous manifestations often provide clues to the existence of the underlying deciency. MNDs may be present in at-risk
individuals who have impaired absorption or poor dietary intake. The micronutrients that most commonly present with cutaneous
ndings include the B vitamins riboavin, niacin, pyridoxine, biotin, and vitamin B12; vitamin C; the fat-soluble vitamins A, E,
and K; the minerals zinc, iron, copper, and selenium; and essential fatty acids. This review will highlight the most common clinical
hair, skin, and nail presentations associated with MNDs and an approach to their treatment. (Nutr Clin Pract. 2019;34:490–503)

hair; micronutrients; micronutrient deciencies; mineral deciency; nails; skin; vitamin deciency

Introduction Etiology of Micronutrient Deciency

Cutaneous abnormalities involving the skin, hair, and nails Malabsorptive conditions such as inammatory bowel dis-
are commonly seen in patients with micronutrient decien- ease, short bowel syndrome, and celiac disease can lead
cies (MNDs) and often provide clues to the underlying de- to deciency in all the micronutrients discussed in this
ciency. Although uncommon among healthy individuals in article.1,3 Deciency of the fat-soluble vitamins and EFAs
resource-rich countries such as the United States, MNDs are can also occur in premature infants, patients with cystic
frequently present in at-risk individuals who have impaired brosis and other causes of exocrine pancreatic insuf-
absorption or poor dietary intake. The micronutrients that ciency, patients who take medications that cause chronic
most commonly present with cutaneous ndings include diarrhea or that interfere with micronutrient or fat absorp-
the B vitamins riboavin, niacin, pyridoxine, biotin, and tion, and patients with chronic cholestatic liver disease such
vitamin B12; vitamin C; the fat-soluble vitamins A, E, as in primary biliary cholangitis and primary sclerosing
and K; the minerals zinc, iron, copper, and selenium; and cholangitis. 3 Alcoholics, particularly those with restricted
essential fatty acids (EFAs). The greatest risk factors for eating, are at increased risk of deciency of niacin, vitamin
MND in the U.S. include the presence of chronic medical B6, biotin, vitamin C, vitamin E, and zinc. 1 Long-term use
disorders including malabsorptive conditions, pancreatic of parenteral nutrition (PN) has been linked to MND of
insufciency, or end-stage renal disease and those who have vitamin K, zinc, iron, copper, and EFAs if supplementation
restricted diets or decreased access to food.1,2 Many of the is not provided.3 A number of medications also interfere
physical signs that will be discussed in this paper can also with micronutrient absorption and will be discussed further
occur due to non-nutritional factors; therefore, a strong
knowledge of differential diagnoses is important. Although
testing can help differentiate MND from non-nutritional From the 1 A.T. Still University, Mesa, Arizona, USA; and the 2 Mayo
causes, the lack of availability of the most accurate tests Clinic, Scottsdale, Arizona, USA.
among labs can decrease the provider’s diagnostic ability. Financial disclosure: None declared.
Despite this, healthcare providers should be knowledgeable Conicts of interest: None declared.
of the cutaneous manifestations of MND in order to make This article originally appeared online on May 29, 2019.
an early diagnosis with adequate intervention.
Corresponding Author:
In this review, we will highlight the most common clinical Michelle DiBaise, DHSc, PA-C, DFAAPA, 5850 E Still Circle, Mesa,
hair, skin, and nail physical ndings associated with MND AZ 85206, USA.
and an approach to their treatment. Email:
DiBaise and Tarleton 491

Table 1. Summary of Cutaneous Manifestations of Micronutrient Deciencies.a

Cutaneous Micronutrient
Manifestation Deciency Causes of Micronutrient Deciency

Diffuse alopecia Biotin, zinc, EFAs Biotin: Malabsorptive disorders, alcohol use disorder, biotinidase deciency,
consumption of large amounts of raw egg whites, pregnant and lactating
Acquired zinc deciency: Malabsorptive disorders, alcohol use disorder,
long-term parenteral supplementation, after GI surgery, chronic liver disease,
chronic renal disease, sickle cell disease, diabetes mellitus, pregnant and
lactating women, exclusively breastfed infants after 6 months of age.
Congenital zinc deciency: Autosomal recessive disorder
EFA: Malabsorptive disorders, pancreatic insufciency, severe cholestatic

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diseases, medication use that interferes with fat absorption, resection of the
distal jejunum and ileum, bariatric surgery, marked restriction of fat in diet,
long-term PN without intravenous fat emulsion
Kinky hair syndrome Copper Gastric bypass or gastrectomy, premature infants on milk formulas without
copper, chronic zinc ingestion, treatment for Wilson’s disease, Menkes disease
Cheilitis, stomatitis, Riboavin, Both riboavin, vitamin B6 and vitamin B12: Malabsorptive disorders, alcohol
glossitis, seborrheic vitamin B6, use disorder
dermatitis vitamin B12 Riboavin: Long-term antibiotic use
Vitamin B6: Chronic renal insufciency, ESRD, rheumatoid arthritis, medication
use (isoniazid, levo/carbidopa and antiepileptic medications), homocystinuria
Vitamin B12: atrophic gastritis, pernicious anemia
Pellagra dermatitis Niacin Malabsorptive disorders, alcohol use disorder, AIDS, carcinoid syndrome,
(hyperpigmented or medication use (isoniazid, 5-uorouracil, phenobarbital, chloramphenicol),
sunburned skin in Hartnup disease
sun-exposed areas)
Dermatitis of the Biotin Malabsorptive disorders, alcohol use disorder, biotinidase deciency,
central face consumption of raw egg whites, pregnant and lactating women
Scurvy: Gingival Vitamin C Malabsorptive disorders, alcohol use disorder, tobacco smokers, exposure to
inammation, second hand smoke, infants fed evaporated or boiled cow’s milk, iron overload
follicular-based disorders, ESRD
petechiae with
corkscrew hairs,
loose and missing
Phrynoderma Vitamin A, Fat-soluble vitamins and EFA: Malabsorptive disorders, pancreatic insufciency,
(follicular vitamin E, severe cholestatic diseases, medication use that interferes with fat absorption
hyperkeratosis) EFAs (note other causes of EFA above)
Petechiae Vitamin E, Vitamin E: Tobacco smokers, exposure to second-hand smoke
vitamin K Vitamin K: Newborns not treated with vitamin K at birth, use of warfarin (or
similar anticoagulants), long-term antibiotic use
Acrodermatitis Zinc Note causes of zinc deciency above
(perioral, perineal,
and acral areas with
a vesicular or
pustular rash)
Pallor Iron Blood loss: Menstruating women, pregnant women, preterm or low birth-weight
infants, frequent blood donors, malignancies particularly colon cancer, GI
surgeries, chronic heart failure
Desquamation EFAs Note causes of EFA deciency above
Brittle nails Biotin Note causes of biotin deciency above
Koilonychia Iron Note causes of iron deciency above

492 Nutrition in Clinical Practice 34(4)

Table 1. (continued)

Cutaneous Micronutrient
Manifestation Deciency Causes of Micronutrient Deciency

Azure lunula Ceruloplasmin Wilson’s disease

Whitened nail beds Selenium Vegetarians in selenium decient areas, patients on long-term hemodialysis,
long-term PN, chylous loss, phenylketonuria, malabsorption disorders, HIV
References [ 1, 3, 8, 14, 17, 19, 26, 32, 40, 48, 56, 58, 61, 75].
AIDS, acquired immunodeciency syndrome; EFA, essential fatty acid; ESRD, end-stage renal disease; GI, gastrointestinal; HIV, human
immunodeciency virus; PN, parenteral nutrition.

below. A summary of the cutaneous ndings found with

MND and the associated etiologies are provided in Table 1.

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Individuals who, through choice or circumstance, have
severely restricted diets are at increased risk of MND.
Such diets occur among vegans, individuals with anorexia
nervosa, individuals on the autism spectrum who refuse
to eat certain foods, individuals with food allergies and
sensitivities, and individuals who restrict a particular food
from their diet such as dairy (lactose intolerant) or fat. 2,3
Severely restricted diets also occur in individuals who live in
poverty or are homeless. 2,4 An estimated 12% of U.S. house-
holds suffer from food insecurity. 4 Individuals with food
insecurity are more likely to eat calorie-dense, low-nutrient
foods. Pregnant women, infants, and older persons with Figure 1. Cheilitis: cracking along the lips or at the angle of
food insecurity are at higher risk of developing MNDs. 4 the lips. Photo courtesy of Alessandro Grandini Adobe Stock

Vitamins are substances that are required for normal growth absorbed in the proximal small intestine and is metabolized
and metabolism, cannot be synthesized by humans, and by the liver or can be complexed to form avoproteins. 7,8
therefore require dietary intake. The exception is vitamin Commensal lactic acid bacteria present in the large intestine
D, which to some extent can be produced through exposure can also produce riboavin, which can be absorbed.1,8
to sunlight in addition to dietary intake. The vitamins are Insufciency can occur in patients who avoid dairy products,
divided into fat soluble (A, D, E, and K) and water soluble as this is a major source of the vitamin. 1,7,8 Deciency can
(B vitamins and C). Fat-soluble vitamins require adequate occur in patients with malabsorptive disorders, in alcohol
fat digestion and absorption and are stored in appreciable use disorder, and in patients with anorexia nervosa.1,7,8
amounts in the liver and adipose tissue. For this reason, Deciency of riboavin can manifest as changes to
excess intake can lead to toxicity. In contrast, water-soluble the mucous membranes, including pharyngitis, cheilitis
vitamins are minimally stored in tissues, and excess levels are (Figure 1), stomatitis (Figure 2), and glossitis (Figure 3). 1,7-9
rapidly excreted in urine. Toxicity is therefore uncommon, There is also an increased incidence of seborrheic dermatitis
except in patients with chronic kidney disease who are at risk in riboavin deciency (Figure 4).9 As an isolated nd-
of pyridoxine and folic acid toxicity. 5 Isolated deciencies of ing, seborrheic dermatitis may not trigger a consideration
just 1 of the water-soluble vitamins are also uncommon. As of vitamin deciency because of the ubiquitous nature
such, supplementation of all water-soluble vitamins is gen- of “dandruff.” Testing, however, should be considered in
erally warranted when a deciency of just 1 is diagnosed.1 patients who have extensive involvement of disease or are
resistant to treatment with over-the-counter dandruff med-
ications (selenium sulde, zinc pyrithione, and ketoconazole
B Vitamins shampoos).
Riboavin, Flavin Mononucleotide, and Flavin Testing for deciency is best assessed through the
erythrocyte glutathione reductase activity coefcient
Adenine Dinucleotide (Vitamin B2)
(EGRAC); however, it should be recognized that this test
Dietary sources substantial in riboavin include dairy, eggs, cannot be utilized in patients with glucose-6-phosphate
sh, meat, poultry, and fortied cereals. 6 Riboavin is dehydrogenase (G6PD) deciency.7,8 A level >1.4 is
DiBaise and Tarleton 493

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Figure 2. Stomatitis. Photo courtesy of vchalup Adobe Stock
images. Figure 4. Seborrheic dermatitis: greasy yellow scale with a
predilection for the hair-bearing areas of the face and scalp.
Photo courtesy of joey333 Adobe Stock images.

Niacin, Nicotinamide, and Nicotinic Acid

(Vitamin B3)
Niacin is commonly found in animal-based food, grains,
nuts, and legumes.14 Niacin can also be converted from
tryptophan (Trp)1 found in poultry, nuts, seeds, soybeans,
legumes, and beef.6 Synthesis of 1 mg of niacin requires
60 mg of dietary Trp, depending on individual circum-
stances such as pregnancy.6,14 Niacin is absorbed in the
small intestine and metabolized by the liver.14 Trp is also
converted to niacin in the liver and requires the pres-
ence of vitamin B6. Niacin deciency can occur after
bariatric surgery, in malabsorptive disorders, in alcohol
Figure 3. Glossitis photo courtesy of meryll Adobe Stock
images. use disorder, and in patients with acquired immunode-
ciency syndrome.14 Trp can also be decient in patients
with vitamin B6 deciency; in carcinoid syndrome, as Trp
is diverted from making niacin in favor of serotonin; in
consistent with riboavin deciency.7 For patients with patients on certain medications that decrease the liver
G6PD deciency, a 24-hour urine for riboavin may assist enzymes necessary for the conversion of Trp to niacin (eg,
in the diagnosis of deciency.8 An alternative test is a serum isoniazid, 5-uorouracil, phenobarbital, chloramphenicol);
riboavin level, which is less sensitive than EGRAC and is and in the autosomal recessive disorder Hartnup disease.1,14
performed after an overnight 12-hour fast, with a normal Deciency of niacin and/or Trp can manifest clinically as
range of 4–24 g/dL.10 the 4 “Ds” of pellagra: dermatitis, diarrhea, dementia, and
The U.S. recommended dietary allowance (RDA) death. The dermatitis appears as a hyperpigmented rash
for riboavin is 1.3 mg daily for adult men and 1.1 mg (Figure 5) in the sun-exposed areas of the body along with
daily for nonpregnant adult women.11 There are no glossitis.1,14
consensus guidelines for riboavin repletion in the Testing for deciency is best assessed through uri-
setting of deciency. Over-the-counter supplements nary testing of N1-methylnicotinamide and N1-methyl-2-
are widely available in a variety of forms and dosages. pyridone-5-carboxamide.14 Niacin requirements based on
Injections may also be available for those individuals who the RDA for adults are 16 mg/d for adult men and 14 mg/d
cannot tolerate oral supplementation. The tolerable upper for nonpregnant adult women, and the upper limit is
intake level (UL) is not determinable in riboavin, but 35 mg/d for both men and women.11,13 If the diet is low in
caution should be used, as there are reports of long-term niacin, intake of 1 g of Trp, which is equivalent to 100 g
pharmacologic doses (>100 mg) reacting with light leading protein per day, can also meet these requirements. 15 Niacin
to detrimental effects on the ocular lens proteins and the deciency can be treated with oral niacin (as nicotinamide)
retina.12,13 supplementation with doses ranging from 10 to 150 mg/d.16
494 Nutrition in Clinical Practice 34(4)

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Figure 6. Diffuse alopecia. Photo courtesy of srisakorn
Adobe Stock images.

cheilitis, and in severe cases seborrheic dermatitis.1,17 Severe

deciency can also lead to signs of pellagra if Trp-to-niacin
conversion is impaired. 1 Vitamin B6 deciency may also
cause microcytic anemia, depression, peripheral neuropa-
thy, and seizures. 1,17
Testing for deciency is best assessed through plasma,
erythrocyte, or urine levels of the phosphorylated metabo-
lite pyridoxal-5-phosphate.17 The supplementation dose
and route are dependent on the severity of symptoms.
Intravenous dosing is limited to individuals with seizures
secondary to vitamin B6 deciency. Oral doses range from
25 mg to 600 mg/d depending on symptom severity.18 The
Figure 5. Pellagra: hyperpigmented rash on the sun-exposed UL for vitamin B6 is 100 mg/d for adults, and caution
areas of the body. Photo courtesy of Herbert L. Fred, MD, should be used with long-term excessive supplementation
Hendrik A. van Dijk Wikimedia (months to greater than a year), as sensory neuropathies,
movement disorders, and other symptoms have been re-
ported. Simply omitting the supplementation should arrest
The treatment of pellagra is usually treated with 100– these symptoms.13,18
300 mg daily of niacinamide in 3 doses, administered
subcutaneously. Biotin
Pyridoxine, Pyridoxamine, and Pyridoxal Foods high in biotin include organ meats, eggs, sh, meat,
sunower seeds, peanuts, canned mushrooms, and sweet
(Vitamin B6) potatoes. 19,20 Raw egg whites contain a protein, avidin,
Vitamin B6 is commonly found in whole grains, vegetables, that prevents absorption of biotin.19 Biotin is absorbed
nuts, and meats.17 Meat sources have a higher bioavailability in the small intestine. Biotin is bound to proteins in foods
than plant sources. 18 Vitamin B6 is absorbed in the jejunum, and becomes bioavailable through the enzymatic action
metabolized by the liver, and excreted in the urine. 17 The of biotinidase. 19 Gut bacteria also synthesize biotin as a
RDA for Vitamin B6 is 1.3–1.7 mg daily for adult men by-product, an additional source of biotin to the host.22
and 1.3–1.5 mg daily for nonpregnant adult women. 11 In Biotin that is not absorbed in the gastrointestinal (GI)
addition to malabsorptive diseases and alcohol use disorder, tract is excreted in the feces, whereas absorbed serum
deciency can occur in patients with chronic renal insuf- biotin is excreted through the kidney. 22 In addition to
ciency and end-stage renal disease; autoimmune disorders, malabsorptive diseases and alcohol use disorder, deciency
particularly rheumatoid arthritis; medication use (isoniazid, can occur in patients with biotinidase deciency, individuals
levo/carbidopa, and antiepileptic medications); and with consuming large amounts of raw egg whites, and pregnant
genetic disorders such as homocystinuria.17 Deciency of and lactating women.19 Deciency of biotin can manifest as
vitamin B6 can manifest cutaneously as stomatitis, glossitis, alopecia (Figure 6), brittle nails (Figure 7), and dermatitis,
DiBaise and Tarleton 495

or lactating and their infants. 26,27 Pernicious anemia is

an autoimmune disorder that leads to a loss of IF, thus
interfering with vitamin B12 absorption.
Deciency of vitamin B12 can manifest as a megaloblas-
tic anemia, weight loss, peripheral neuropathy, depression,
dementia, cheilitis (Figure 1), stomatitis (Figure 2), and
glossitis (Figure 3).26 Patients with vitamin B12 deciency
may initially present with glossitis and not show signs of
anemia early on.28 Testing for deciency is best assessed
through serum or plasma vitamin B12 levels. 26 Levels <170–
250 pg/mL are consistent with vitamin B12 deciency.26
An alternative test is methylmalonic acid (MMA), in which
an elevated level (>0.4 mol/L) indicates vitamin B12

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Figure 7. Brittle nails. Photo courtesy of ALAIN Treatment of vitamin B12 deciency is imperative,
VERMEULEN Adobe Stock images. as neurologic impairment can be irreversible if left
untreated.28,29 Studies show that high-dose oral vitamin B12
supplements can be just as effective as injections. 28-30 With
particularly involving the face.19 Patients may also experi-
high-dose oral supplements (1000–2000 g daily), 1%–2%
ence myalgias, paresthesias, and mental status changes.19
of vitamin B12 is absorbed through passive diffusion in an
Testing for deciency is best assessed through measure-
IF-independent process and is enough to meet the daily
ment of white blood cell biotinylated methylcrotonyl CoA
need.29 Nevertheless, there continues to be uncertainty of
carboxylase and propionyl-CoA carboxylase. Alternatively,
oral vitamin B12 supplementation in deciency, as it may
biotin levels in serum and urine can be measured.19 There
not improve serum MMA levels, as well as intramuscular
are no set recommendations for biotin supplementation,
(IM) or subcutaneous therapy.27 The American Society of
and dosage and duration of supplementation vary. 21 Due
Hematology does not have specic guidelines on oral vs
to the lack of data, there is no UL for biotin, nor is
IM injections for vitamin B12 replacement, except in the
there an RDA; instead, the recommendations are provided
presence of neurologic impairment.30 The British Society
as adequate intake (AI).11,13 The AI is 30 g daily for
for Haematology recommends vitamin B12 IM injections
adults, and a typical varied diet generally provides sufcient
for severe deciency and in patients with malabsorption
amounts of biotin. Many people supplement their diets with
and to reserve oral supplementation for patients who are
additional biotin up to 500–1000 g/d.21 High doses of
compliant, asymptomatic, and have normal absorption with
biotin, however, may cause falsely elevated thyroxine and
mild deciency.27 A common dose for repletion in decient
triiodothyronine levels, mimicking Grave’s disease23,24 or a
adults is 1000 g cyanocobalamin IM injection once per
falsely low troponin level.25
week until the deciency is corrected.31 Recommendations
for IM injections for treatment of pernicious anemia range
Vitamin B12 from 100 to 1000 g cyanocobalamin for 5 days and then
Dietary sources substantial in vitamin B12 include animal 100–1000 g on a monthly basis. 31 Vegans and strict vege-
products, particularly meat, sh, dairy products, and eggs, tarians should be intentionally consuming fortied cereals
but B12 is also present in fortied cereals.6,26 The RDA for on a regular basis and/or take a vitamin B12 supplement. 27
vitamin B12 is 2.4 g/d for adult men and nonpregnant
women with no UL, as it is not determinable.11,13 Vitamin
Ascorbic Acid (Vitamin C)
B12 bound to protein requires release through the action
of gastric acid and proteases, but this step is not necessary Dietary sources rich in vitamin C include citrus fruits, a
when vitamin B12 is in the form of supplements or fortied variety of peppers, tomato sauce, fortied juices, broccoli,
cereals.26 Vitamin B12 is absorbed in the distal ileum after spinach, strawberries, and potatoes.6 Vitamin C is absorbed
binding with intrinsic factor (IF), a protein secreted by in the distal small intestine and excreted by the kidneys.32
the parietal cells of the stomach. Deciency can occur in Vitamin C is necessary for collagen synthesis.1,32,33 In ad-
patients with achlorhydria, atrophic gastritis, celiac disease, dition to malabsorptive diseases and alcohol use disorder,
or Crohn’s disease; after bariatric surgery or resection deciency can occur in both tobacco smokers and individ-
of the distal ileum; patients on metformin (>4 months); uals exposed to second hand smoke, in infants fed predom-
use of proton pump inhibitors or histamine H2 blockers inantly evaporated or boiled cow’s milk, in patients with
(>12 months); adults older than 75 years; and in vegans iron overload such as from hemolysis, and in patients with
or strict vegetarians, particularly those who are pregnant end-stage renal disease on hemodialysis.1,32,33 Deciency
496 Nutrition in Clinical Practice 34(4)

and up to 1000 mg daily for adults.34 Vitamin C doses of

300 mg daily for 1 month should be sufcient replenishment
to decrease symptoms and for 3 months for a full recovery
from scurvy. 35,36 An alternative supplementation regimen
for adults includes 2 g daily for 3 days followed by 500 mg
daily for a week then 100 mg daily for up to 3 months. 34 Dis-
advantages of high-dose vitamin C supplementation may
include falsely elevated blood glucose levels in point-of -care
glucose monitors and potential oxalate nephropathy. 37,38 In
addition, vitamin C absorption decreases by at least half
when doses above 1 g/d are administered.39

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Retinol, Retinal, Retinyl Esters (Vitamin A),
and Provitamin A Carotenoids
Food sources high in vitamin A include beef, poultry, and
vegetables such as sweet potato, carrots, spinach, pump-
kin, and butternut squash. 6 The fat-soluble vitamin A is
Figure 8. Gingival inammation with tooth loss seen in absorbed in the small intestine with the aid of pancreatic en-
scurvy. Image is from page 285 of Modern surgery, general and zymes and bile salts. Deciency can occur with maldigestive
operative (1919) (no known copyright restrictions). and malabsorptive disorders, pancreatic insufciency, severe
cholestatic diseases, and with medication use that interferes
with fat absorption.1,3,40 Vitamin A is a component of
the protein rhodopsin, is necessary for vision, and aids
in differentiation and functioning of the conjunctiva and
cornea.40 Deciency will manifest as impaired night vision
and xerophthalmia.1,2,40 Over time, severe deciency can
lead to complete blindness. In addition to visual problems,
deciency of vitamin A can cause phrynoderma or hyperk-
eratosis at the hair follicles, decreased immunity, and poor
bone growth. 1,40 In addition to vitamin A, data support
a link between phrynoderma and deciencies of the B
vitamins, vitamin E, EFAs, and general malnutrition.41,42
Testing for vitamin A deciency is best accomplished
through measurement of plasma retinol and carotenoid
levels. 40 The RDA for vitamin A for adult males is 3000 IU
(900 g retinol) daily and for females 2300 IU (700 g
retinol) daily. 6,43 There are no set guidelines for treating
Figure 9. Follicular-based petechiae with corkscrew hairs seen
in scurvy. Photo courtesy of DermNet New Zealand. phrynoderma.44 IM injections including vitamin A and/or B
complex vitamins along with EFAs have been recommended
in the treatment of phrynoderma.44 The World Health
of vitamin C can manifest as scurvy with fatigue, gingival Organization recommendation for the treatment of vitamin
inammation (Figure 8), follicular-based petechiae with A deciency with xerophthalmia includes immediate use
corkscrew hairs (Figure 9), poor wound healing, joint pain, of oil-based oral vitamin A of 200,000 IU, with a repeat
and thickening of the skin (hyperkeratosis).1,32,33 Patients dose on days 2 and 14. Subsequent supplementation with
may also experience tooth loss, depression, bone disease, doses of 200,000 IU is recommended every 4–6 months.45
and iron deciency anemia from bleeding. 1,32,33 Water-miscible vitamin A is an alternative form used in
Testing for deciency is best assessed through measure- individuals with fat malabsorption disorders. 46 The UL for
ment of serum or leukocyte vitamin C levels.1,32,33 In healthy vitamin A is 10,000 IU (3000 g) daily for adult men and
individuals, the RDA for vitamin C is 90 mg/d for men and 10,000 IU (3000 g) daily for nonpregnant adult women.43
75 mg/d for women with the UL being 2000 mg daily for Acute vitamin A toxicity can occur in adults with a dose
both adult men and women. 11,13 Replenishment of vitamin of >660,000 IU (>200 mg).47 Chronic toxicity can occur
C deciency may require up to 300 mg daily in pediatrics with long-term ingestion of high-dose vitamin A. Vitamin
DiBaise and Tarleton 497

mended when using high-dose vitamin E supplementation,

as there have been studies to suggest an increase in all-cause

Phylloquinone and Menaquinones (Vitamin K)

Food sources of vitamin K include liver, green leafy veg-
etables, broccoli, peas, and green beans.6 Vitamin K is also
produced by bacteria in the gut.55 Vitamin K is absorbed
in the small intestine and, like vitamins A and E, is fat
soluble and requires pancreatic enzymes and bile salts for
absorption, transport, and storage in the liver. Vitamin K is
necessary for clotting, serving as a cofactor for key proteins
in the coagulation cascade (Factors II, VII, IX, and X).55

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Figure 10. Petechiae can be associated with vitamin K and Vitamin K is also a cofactor in osteocalcin, important in
less commonly vitamin E deciencies. Photo courtesy of bone mineralization.55 In addition to malabsorptive dis-
drpilulkin Adobe Stock images. orders, pancreatic insufciency, severe cholestatic diseases,
and medication use that interferes with fat absorption,
deciency of vitamin K has been associated with newborns
A is potentially teratogenic during the rst trimester of not receiving vitamin K at birth, use of warfarin (or sim-
pregnancy at doses above the RDA. 47 ilar anticoagulants), and antibiotic use which can destroy
gut bacteria that produce vitamin K. 55,56 Bleeding is the
α-Tocopherol (Vitamin E) typical clinical presentation in vitamin K deciency. Pe-
Vitamin E is commonly found in nuts, green leafy veg- techiae and purpura are common cutaneous manifestations
etables, fortied cereals, and vegetable oils.48 Vitamin E is (Figure 10).
absorbed in the small intestine and, like vitamin A, is fat Testing for deciency is best assessed through measure-
soluble and requires pancreatic enzymes and bile salts for ment of prothrombin time (PT)/international normalized
absorption, transport, and storage in the liver. In addition ratio (INR), as mild deciency will affect Factor VII
to malabsorptive disorders, pancreatic insufciency, severe rst.55,56 In severe deciency, both PT and partial thrombo-
cholestatic diseases, and with medication use that interferes plastin time can be affected. In this instance, measurement
with fat absorption, deciency can occur in both tobacco of vitamin K–dependent proteins (Factor II [prothrombin],
smokers and individuals exposed to second hand smoke.48 VII, IX, X, and/or protein C) will guide the diagnosis.55,56
A deciency of vitamin E has been associated with the The AI for vitamin K in men is 120 g and in women
development of lipofuscin, a ceroid pigment that can lead to is 90 g/d; the UL is not determinable.11,13 There are no
brown deposits in tissues, specically bowel, muscle tissue, standard guidelines for treating vitamin K deciency, but
and the retina.48 In addition to ceroid pigment deposits, supplementation regimens range from 2.5 to 10 mg, twice
patients with vitamin E deciency can develop hemolysis weekly to daily with oral or injected forms. Because the
with petechiae (Figure 10), ataxia, and other neuropathies.48 amount of vitamin K in lipid injectable form varies depend-
Testing for deciency is best accomplished through mea- ing on the composition in the manufacturing process, care
surement of serum α-tocopherol levels when serum lipid should be taken to monitor dosing with injectable forms.56
levels are normal. In hyperlipidemia, the α-tocopherol level It is important to remember that warfarin and vitamin K
must be divided by the total lipids (cholesterol + triglyc- are antagonists; therefore, once the goal INR is met, daily
erides). A value >0.8 mg is considered normal.48 The RDA vitamin K intake should remain consistent. An increase in
for vitamin E in adults is 15 mg/d of dietary α-tocopherol vitamin K intake without adjustment of warfarin may lead
with the UL being 1000 mg/d.11,13 Therapeutic replacement to an increased risk of clotting.53
dosing of vitamin E is not well dened. In adults, treatment
with oral vitamin E ranges from 200 to 2000 mg/d.49 Water- Minerals
miscible vitamin E (tocopheryl polyethylene glycol succi-
nate) is an alternative form used in cholestatic conditions
and is available over-the-counter in the United States.50 Dietary sources rich in zinc include beef, sh, oysters, liver,
There are mixed data about consuming high doses of beans, and soybeans. 6 Zinc is also present in over-the-
vitamin E (>1200 mg/d) and the risk of competition with vi- counter cold lozenges and denture adhesive. 57 The RDA for
tamin K, increased bleeding for patients receiving warfarin, zinc is 11 mg daily for adult men and 8 mg daily for non-
and a decrease in platelet adhesion. 49,53,54 Caution is recom- pregnant adult women, with the UL being 40 mg daily for
498 Nutrition in Clinical Practice 34(4)

both adult men and women. 58,59 Overuse of these products

can lead to zinc toxicity and subsequent copper deciency,
as the 2 compete for absorption. Zinc is predominantly
absorbed in the duodenum and jejunum but also occurs in
the ileum and large intestine. 57 Zinc is bound to albumin and
transported to the liver. It is excreted mainly by the GI tract.
In addition to malabsorptive disorders, alcohol use disorder,
and long-term PN without added zinc, acquired zinc de-
ciency can be found in patients after GI surgery, chronic liver
disease, chronic renal disease, chronic diarrhea, sickle cell
disease, diabetes mellitus, pregnant and lactating women,
and exclusively breastfed infants after 6 months of age. 1,57
A congenital zinc deciency due to an autosomal recessive

Printed by [Wiley Online Library - - /doi/epdf/10.1002/ncp.10321] at [24/01/2021].

disorder affecting zinc absorption presents in infancy with
acrodermatitis enteropathica.1,57 Zinc deciency, whether Figure 12. Perianal dermatitis associated with zinc deciency
acquired or congenital, can lead to alopecia, dermatitis, Photos courtesy of Dr. Mark Pittelkow, Mayo Clinic
diarrhea, anorexia, dysgeusia, impaired immune function, Department of Dermatology.
infertility issues, and growth retardation.1,57 The dermatitis
associated with zinc deciency affects the perioral, per-
ineal, and acral areas with a vesicular or pustular rash
(Figures 11–13).1,2,57
Testing for deciency is best assessed through
measurement of plasma or serum zinc levels; however, these
tests are not always accurate in measuring deciency. 1,57 It
is recommended that clinical correlation with laboratory
results and presence of risk factors assist in the
Oral replacement is 2–3 mg/kg/d of elemental zinc, which
will generally alleviate all clinical manifestations within 1–
2 weeks. Patients with acrodermatitis enteropathica require
oral supplementation of 1–2 mg/kg/d for life. 34 Large doses
of zinc have been shown to cause side effects includ-
ing gastric irritation with nausea, vomiting, and gastric Figure 13. Acral dermatitis associated with zinc deciency
hemorrhage. 34 Because zinc competes with copper absorp- Photos courtesy of Dr. Mark Pittelkow, Mayo Clinic
tion, copper levels should be monitored during long-term Department of Dermatology.
zinc repletion.
Heme iron is commonly found in meat, poultry, and sh,
and non-heme iron is found in vegetables, fruits, and forti-
ed products.6 Heme iron has 2 times better absorption than
non-heme iron, and both can be enhanced by concomitant
intake of vitamin C. 60 Iron is predominantly absorbed in the
duodenum, and excess is stored as ferritin or hemosiderin
in the liver, spleen, and bone marrow or in the muscle
as myoglobin.60 Iron is eliminated in the urine, feces, GI
tract, skin, and through blood loss. The RDA for iron is
8 mg/d for adult men, 18 mg/d for women between 18
and 50 years old, and 8 mg/d for women between 51 and
70 years old (both nonpregnant), with UL being 45 mg/d
for both men and women.58,59 Iron deciency can be found
Figure 11. Perioral dermatitis associated with zinc deciency. in menstruating women; pregnant women; preterm or low-
Photos courtesy of Dr. Mark Pittelkow, Mayo Clinic birth-weight infants; frequent blood donors; poor intake,
Department of Dermatology. especially among vegan and vegetarian diets; in patients
DiBaise and Tarleton 499

Figure 15. Kayser-Fleischer rings associated with Wilson’s

Printed by [Wiley Online Library - - /doi/epdf/10.1002/ncp.10321] at [24/01/2021].

disease Photo courtesy of Herbert L. Fred, MD, Hendrik A.
van Dijk Wikimedia.

Figure 14. Koilonychia associated with iron-deciency anemia (sodium ferric gluconate), and Feraheme (ferumoxytol).
Photo courtesy of CHeitz (Flickr). Hypersensitivity reactions can occur with any of these
preparations; therefore, they should be administered where
with malignancies, particularly colon cancer; in patients
the patient can be closely monitored with resuscitation
who have had GI surgeries; and patients with chronic
equipment and personnel trained to respond to an
heart failure.60 Iron deciency can lead to a microcytic,
anaphylactic reaction.62-66 There is currently no form of
hypochromic anemia with associated pallor along with fa-
parenteral iron that is suitable for addition to PN in the U.S.
tigue, exertional dyspnea, koilonychia (spoon-shaped nails)
(Figure 14), and developmental delays in children.60
Deciency is generally considered in the setting of mi-
crocytic, hypochromic anemia determined by a complete Beef, soy, nuts, seeds, beans, shellsh, and mushrooms
blood count. 60 This is, however, not specic for iron de- are all good sources of dietary copper. 6 The RDA for
ciency, whereas iron studies that may include serum iron copper is 900 g/d for adult men and for nonpregnant
level, total iron binding capacity, transferrin, serum ferritin, adult women, with the UL being 10,000 g/d.58,59 Copper
and transferrin saturation will allow for a more specic is absorbed in the stomach and proximal small intestine
diagnosis of iron deciency.60 With inammatory reactions and is decreased in the presence of iron, zinc, and vita-
(acute-phase reaction), transferrin and serum iron levels min C.67 Copper is transported to the liver where it is
may decrease, whereas serum ferritin levels may increase. bound to ceruloplasmin for transport to tissues.67 Copper
This contradictory pattern of lab ndings should lead is eliminated in the GI tract, predominantly in bile. Copper
the provider to investigate for an underlying inammatory deciency can be found in patients who have undergone
process or infection. gastric bypass or gastrectomy, premature infants on milk
Oral iron supplementation is generally considered rst formulas without copper, in patients with chronic excess zinc
in the treatment of iron deciency. Iron sulfate is most ingestion, and in patients overtreated for Wilson’s disease.68
frequently used; however, iron gluconate and iron fumarate Wilson’s disease is a deciency in ceruloplasmin leading to
are also good alternatives. Recommended dosing for adults excessive copper deposits in multiple organs. Classic signs
is 100–200 mg of elemental iron. 61 Divided doses in between are azure lunula and Kayser-Fleischer rings of the eyes
meals with a vitamin C source will optimize absorption. (Figure 15).69 A rare X-linked disorder, Menkes disease,
Repletion of iron stores and normalization of serum ferritin results in copper deciency due to inability to absorb copper
will typically occur within 3–6 months of treatment. Adher- from the intestine. Copper deciency leads to abnormally
ence to treatment may be compromised by side effects such formed hair (kinky hair syndrome) (Figure 16), skin de-
as nausea, vomiting, constipation, and a metallic taste. If pigmentation (Figure 17), ataxia, myeloneuropathy, and
treatment with oral iron fails, including premature termi- hepatosplenomegaly.70 The signs and symptoms of Menkes
nation of treatment, lack of adequate adherence with the disease are similar to acquired copper deciency, except
regimen, or a refractory response to treatment, parenteral Menkes is more severe and diagnosed early in infancy with
iron should be initiated.61 associated developmental delay, epilepsy, and progressive
There are 5 forms of parenteral iron available in neurologic symptoms.70
the United States: INFeD (iron dextran), Venofer (iron Testing for deciency is accomplished by measurement
sucrose), Injectafer (ferric carboxymaltose), Ferrlecit of serum copper and ceruloplasmin levels; however, like
500 Nutrition in Clinical Practice 34(4)

Printed by [Wiley Online Library - - /doi/epdf/10.1002/ncp.10321] at [24/01/2021].

Figure 18. Whitened nail beds associated with selenium
deciency. Photo courtesy of viiwee Adobe Stock images.

Bariatric Surgery recommends routine copper supplemen-

tation (1–2 mg/d for those who have undergone Roux-en-Y
gastric bypass and 2 mg/d after biliopancreatic diversion).73
Figure 16. Kinky-hair syndrome associated with Menkes Recommendations for copper supplementation for mild-to-
disease Photo courtesy of Datta AK, Ghosh T, Nayak K, moderate deciency are oral copper 3–8 mg/d until levels
Ghosh M. Menkes kinky hair disease: A case report. Cases J. are corrected and, in the setting of severe symptomatic
1, 1, 158. 2008. deciency, 2–4 mg/d of intravenous copper for 6 days
(Wikimedia). then switching to oral therapy. Hematologic abnormalities
should reverse within 4–12 weeks of therapy, with serial
assessment of serum copper.71-73 Treatment of Menkes
disease consists of parenteral administration of a copper-
histidine complex.69

Poultry, nuts, seeds, wheat, barley, beef, and potatoes are all
good sources of selenium; however, there is variability of
selenium in food sources based on the amount of selenium
in the soil used to grow foods.6 The RDA for selenium
is 55 g/d for adult men and nonpregnant women, with
the UL being 400 g/d. 58,59 Selenium is absorbed in the
small intestine and is excreted in the urine.74 In areas of
the world where low levels of selenium exist in the soil,
Figure 17. Skin depigmentation associated with copper deciency is more common. This is particularly true for veg-
deciency Photo courtesy of 
C A. Bueckert Adobe Stock
etarians living in selenium-decient areas. 74 Deciency may
also occur in patients on long-term hemodialysis; receiving
long-term PN; having chylous loss, phenylketonuria, or
ferritin, both are also acute-phase reactants and can be malabsorption disorders; and in individuals with HIV.74-77
elevated in the presence of inammatory processes.69,70 Selenium deciency leads to whitened nailbeds (Figure 18),
Treatment of Wilson’s disease consists of avoidance of impaired immune function, and skeletal myopathy. Patients
high-copper foods and copper chelation.69 In early stages, receiving long-term PN without selenium supplementation
high doses of zinc may be effective in delaying the onset may develop cardiomyopathy.76
of symptomatic disease, as zinc competes with copper for Testing for deciency is generally accomplished through
absorption in the GI tract. Copper can be administered measurement of serum or plasma selenium levels, although
orally or intravenously for deciency; however, there are no selenium levels in hair and nails can provide a more accurate
set recommendations regarding dose, route, or monitoring long-term assessment of intake. The optimal dose and dura-
parameters. 71,72 The American Society for Metabolic and tion of selenium supplementation is not well established.77
DiBaise and Tarleton 501

least 10% of total calories from fat of which 2%–4% are

from linoleic acid. Intravenous lipid emulsion (ILE) (100 g
soybean oil-based ILE) per week should be adequate to
prevent deciency with higher doses needed in patients
with preexisting deciency.3 In patients with pancreatic
insufciency, appropriate pancreatic enzyme replacement is
essential to ensure that EFA replacement will not worsen fat

Although MNDs are uncommon in the general population,
a number of conditions are at risk of these deciencies,
including those patients with restricted diets; chronic med-

Printed by [Wiley Online Library - - /doi/epdf/10.1002/ncp.10321] at [24/01/2021].

ical disorders including malabsorptive conditions, pancre-
Figure 19. Desquamation associated with deciency of atic insufciency, or end-stage renal disease; and use of
essential fatty acids. Photo courtesy of nataba Adobe Stock medications that interfere with absorption, metabolism,
storage, and excretion of micronutrients. In addition, in
those patients dependent on PN, it is important to recognize
that the recent development of shortages of parenteral
A common dose of oral selenium for adults is 100 g/d.78 products including micronutrients may also contribute to
The amount of selenium in multi-trace element (MTE) deciencies.81 Shortages require thorough communication
formulations for PN vary by age group (neonate, pediatric, and a team approach to care. In this setting, oral and enteral
and adult). The standard amount of selenium that is present routes of therapy should be attempted whenever possible,
in MTE-5 for adults is 60 g, whereas the recommended reserving parenteral multivitamin and trace elements for
amount for neonates and pediatric populations is based those who are entirely PN dependent.82
on weight. Importantly, the MTE-4 formulation does not MNDs frequently lead to abnormalities of the skin, hair,
contain selenium.39 and nails, which can serve as early warning signs for de-
ciency. An awareness of these changes allows the healthcare
EFA Deciency (Linoleic and α-Linolenic provider to intervene with conrmation of the diagnosis
Acids) and implementation of adequate supplementation as well
as identication and treatment of the underlying disorder
Linoleic acid and α -linolenic acid cannot be synthesized
causing the deciency.
by humans and are considered EFAs and are required in
the diet.3,79 EFAs are commonly found in ingested fats and
oils including corn, soy, and safower.3 EFAs are absorbed Statement of Authorship
in the distal jejunum and ileum, then packaged and trans- M. DiBaise and S. M. Tarleton equally contributed to the
ported to the liver, muscle, and adipose tissue. 3 In addition conception and design of the work; M. DiBaise and S. M.
to malabsorptive disorders, pancreatic insufciency, severe Tarleton contributed to the design of the manuscript; M.
cholestatic diseases, and with medication use that interferes DiBaise and S. M. Tarleton contributed to the acquisition
with fat absorption, EFA deciency can occur in patients and analysis of the data; M. DiBaise and S. M. Tarleton
with resection of the distal jejunum and ileum or following contributed to the interpretation of the data; and M.
bariatric surgery, in patients with marked restriction of fat in DiBaise and S. M. Tarleton drafted the manuscript. All
their diet, and in patients on long-term PN who are unable authors critically revised the manuscript, agree to be fully
to receive intravenous fat emulsion.3 Deciency of EFAs accountable for ensuring the integrity and accuracy of the
leads to desquamation (Figure 19) and dermatitis, alopecia, work, and read and approved the nal manuscript.
poor growth in infants and children, poor wound healing,
and thrombocytopenia.3 Supplementary Information
Testing for deciency is accomplished by measurement Additional supporting information may be found online in the
of the serum triene-tetraene ratio.3 In the absence of linoleic Supporting Information section at the end of the article.
acid and α-linolenic acid, oleic acid is converted into mead
acid (triene) with subsequent downregulated production of
arachidonic acid (tetraene). 80 An elevated triene-tetraene References
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