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 Deficiency Parenteral and Enteral Nutrition

DOI: 10.1002/ncp.10321
wileyonlinelibrary.com

Michelle DiBaise, DHSc, PA-C, DFAAPA1 ; and Sherry M. Tarleton,

RDN, CNSC2

Abstract
Micronutrient deficiencies (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 deficiency. MNDs may be present in at-risk
individuals who have impaired absorption or poor dietary intake. The micronutrients that most commonly present with cutaneous
findings include the B vitamins riboflavin, 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)

Keywords
hair; micronutrients; micronutrient deficiencies; mineral deficiency; nails; skin; vitamin deficiency

Introduction Etiology of Micronutrient Deficiency

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

Table 1. Summary of Cutaneous Manifestations of Micronutrient Deficiencies.a

Cutaneous Micronutrient
Manifestation Deficiency Causes of Micronutrient Deficiency

Hair
Diffuse alopecia Biotin, zinc, EFAs Biotin: Malabsorptive disorders, alcohol use disorder, biotinidase deficiency,
consumption of large amounts of raw egg whites, pregnant and lactating
women
Acquired zinc deficiency: 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 deficiency: Autosomal recessive disorder
EFA: Malabsorptive disorders, pancreatic insufficiency, severe cholestatic
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
Skin
Cheilitis, stomatitis, Riboflavin, Both riboflavin, vitamin B6 and vitamin B12: Malabsorptive disorders, alcohol
glossitis, seborrheic vitamin B6, use disorder
dermatitis vitamin B12 Riboflavin: Long-term antibiotic use
Vitamin B6: Chronic renal insufficiency, 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-fluorouracil, phenobarbital, chloramphenicol),
sunburned skin in Hartnup disease
sun-exposed areas)
Dermatitis of the Biotin Malabsorptive disorders, alcohol use disorder, biotinidase deficiency,
central face consumption of raw egg whites, pregnant and lactating women
Scurvy: Gingival Vitamin C Malabsorptive disorders, alcohol use disorder, tobacco smokers, exposure to
inflammation, second hand smoke, infants fed evaporated or boiled cow’s milk, iron overload
follicular-based disorders, ESRD
petechiae with
corkscrew hairs,
loose and missing
teeth
Phrynoderma Vitamin A, Fat-soluble vitamins and EFA: Malabsorptive disorders, pancreatic insufficiency,
(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 deficiency above
enteropathica
(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 deficiency above
Nails
Brittle nails Biotin Note causes of biotin deficiency above
Koilonychia Iron Note causes of iron deficiency above

(continued)
492 Nutrition in Clinical Practice 34(4)

Table 1. (continued)

Cutaneous Micronutrient
Manifestation Deficiency Causes of Micronutrient Deficiency

Azure lunula Ceruloplasmin Wilson’s disease

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

below. A summary of the cutaneous findings found with

MND and the associated etiologies are provided in Table 1.
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
images.

Vitamins
Vitamins are substances that are required for normal growth
and metabolism, cannot be synthesized by humans, and
therefore require dietary intake. The exception is vitamin
D, which to some extent can be produced through exposure
to sunlight in addition to dietary intake. The vitamins are
divided into fat soluble (A, D, E, and K) and water soluble
(B vitamins and C). Fat-soluble vitamins require adequate
fat digestion and absorption and are stored in appreciable
amounts in the liver and adipose tissue. For this reason,
excess intake can lead to toxicity. In contrast, water-soluble
vitamins are minimally stored in tissues, and excess levels are
rapidly excreted in urine. Toxicity is therefore uncommon,
except in patients with chronic kidney disease who are at risk
of pyridoxine and folic acid toxicity.5 Isolated deficiencies of
just 1 of the water-soluble vitamins are also uncommon. As
such, supplementation of all water-soluble vitamins is gen-
erally warranted when a deficiency of just 1 is diagnosed.1
B Vitamins
Riboflavin, Flavin Mononucleotide, and Flavin
Adenine Dinucleotide (Vitamin B2)
Dietary sources substantial in riboflavin include dairy, eggs,
fish, meat, poultry, and fortified cereals.6 Riboflavin is
absorbed in the proximal small intestine and is metabolized
by the liver or can be complexed to form flavoproteins.7,8
Commensal lactic acid bacteria present in the large intestine
can also produce riboflavin, which can be absorbed.1,8
Insufficiency can occur in patients who avoid dairy products,
as this is a major source of the vitamin.1,7,8 Deficiency can
occur in patients with malabsorptive disorders, in alcohol
use disorder, and in patients with anorexia nervosa.1,7,8
Deficiency of riboflavin can manifest as changes to
the mucous membranes, including pharyngitis, cheilitis
(Figure 1), stomatitis (Figure 2), and glossitis (Figure 3).1,7-9
There is also an increased incidence of seborrheic dermatitis
in riboflavin deficiency (Figure 4).9 As an isolated find-
ing, seborrheic dermatitis may not trigger a consideration
of vitamin deficiency because of the ubiquitous nature
of “dandruff.” Testing, however, should be considered in
patients who have extensive involvement of disease or are
resistant to treatment with over-the-counter dandruff med-
ications (selenium sulfide, zinc pyrithione, and ketoconazole
shampoos).
Testing for deficiency is best assessed through the
erythrocyte glutathione reductase activity coefficient
(EGRAC); however, it should be recognized that this test
cannot be utilized in patients with glucose-6-phosphate
dehydrogenase (G6PD) deficiency.7,8 A level >1.4 is
DiBaise and Tarleton
Figure 2. Stomatitis. Photo courtesy of vchalup Adobe Stock
images.
Figure 3. Glossitis photo courtesy of meryll Adobe Stock
images.
consistent with riboflavin deficiency.7 For patients with
G6PD deficiency, a 24-hour urine for riboflavin may assist
in the diagnosis of deficiency.8 An alternative test is a serum
riboflavin level, which is less sensitive than EGRAC and is
performed after an overnight 12-hour fast, with a normal
range of 4–24 µg/dL.10
The U.S. recommended dietary allowance (RDA)
for riboflavin is 1.3 mg daily for adult men and 1.1 mg
daily for nonpregnant adult women.11 There are no
consensus guidelines for riboflavin repletion in the
setting of deficiency. Over-the-counter supplements
are widely available in a variety of forms and dosages.
Injections may also be available for those individuals who
cannot tolerate oral supplementation. The tolerable upper
intake level (UL) is not determinable in riboflavin, but
caution should be used, as there are reports of long-term
pharmacologic doses (>100 mg) reacting with light leading
to detrimental effects on the ocular lens proteins and the
retina.12,13
493
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 deficiency can occur after
bariatric surgery, in malabsorptive disorders, in alcohol
use disorder, and in patients with acquired immunodefi-
ciency syndrome.14 Trp can also be deficient in patients
with vitamin B6 deficiency; in carcinoid syndrome, as Trp
is diverted from making niacin in favor of serotonin; in
patients on certain medications that decrease the liver
enzymes necessary for the conversion of Trp to niacin (eg,
isoniazid, 5-fluorouracil, phenobarbital, chloramphenicol);
and in the autosomal recessive disorder Hartnup disease.1,14
Deficiency of niacin and/or Trp can manifest clinically as
the 4 “Ds” of pellagra: dermatitis, diarrhea, dementia, and
death. The dermatitis appears as a hyperpigmented rash
(Figure 5) in the sun-exposed areas of the body along with
glossitis.1,14
Testing for deficiency is best assessed through uri-
nary testing of N1-methylnicotinamide and N1-methyl-2-
pyridone-5-carboxamide.14 Niacin requirements based on
the RDA for adults are 16 mg/d for adult men and 14 mg/d
for nonpregnant adult women, and the upper limit is
35 mg/d for both men and women.11,13 If the diet is low in
niacin, intake of 1 g of Trp, which is equivalent to 100 g
protein per day, can also meet these requirements.15 Niacin
deficiency can be treated with oral niacin (as nicotinamide)
supplementation with doses ranging from 10 to 150 mg/d.16
494
Figure 5. Pellagra: hyperpigmented rash on the sun-exposed
areas of the body. Photo courtesy of Herbert L. Fred, MD,
Hendrik A. van Dijk Wikimedia https://cnx.org/content/
m14940/latest/Case_2-pres1-1.jpg.
The treatment of pellagra is usually treated with 100–
300 mg daily of niacinamide in 3 doses, administered
subcutaneously.
Pyridoxine, Pyridoxamine, and Pyridoxal
(Vitamin B6)
Vitamin B6 is commonly found in whole grains, vegetables,
nuts, and meats.17 Meat sources have a higher bioavailability
than plant sources.18 Vitamin B6 is absorbed in the jejunum,
metabolized by the liver, and excreted in the urine.17 The
RDA for Vitamin B6 is 1.3–1.7 mg daily for adult men
and 1.3–1.5 mg daily for nonpregnant adult women.11 In
addition to malabsorptive diseases and alcohol use disorder,
deficiency can occur in patients with chronic renal insuffi-
ciency and end-stage renal disease; autoimmune disorders,
particularly rheumatoid arthritis; medication use (isoniazid,
levo/carbidopa, and antiepileptic medications); and with
genetic disorders such as homocystinuria.17 Deficiency of
vitamin B6 can manifest cutaneously as stomatitis, glossitis,
Nutrition in Clinical Practice 34(4)
Figure 6. Diffuse alopecia. Photo courtesy of srisakorn
Adobe Stock images.
cheilitis, and in severe cases seborrheic dermatitis.1,17 Severe
deficiency can also lead to signs of pellagra if Trp-to-niacin
conversion is impaired.1 Vitamin B6 deficiency may also
cause microcytic anemia, depression, peripheral neuropa-
thy, and seizures.1,17
Testing for deficiency 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 deficiency. Oral doses range from
25 mg to 600 mg/d depending on symptom severity.18 The
UL for vitamin B6 is 100 mg/d for adults, and caution
should be used with long-term excessive supplementation
(months to greater than a year), as sensory neuropathies,
movement disorders, and other symptoms have been re-
ported. Simply omitting the supplementation should arrest
these symptoms.13,18
Biotin
Foods high in biotin include organ meats, eggs, fish, meat,
sunflower seeds, peanuts, canned mushrooms, and sweet
potatoes.19,20 Raw egg whites contain a protein, avidin,
that prevents absorption of biotin.19 Biotin is absorbed
in the small intestine. Biotin is bound to proteins in foods
and becomes bioavailable through the enzymatic action
of biotinidase.19 Gut bacteria also synthesize biotin as a
by-product, an additional source of biotin to the host.22
Biotin that is not absorbed in the gastrointestinal (GI)
tract is excreted in the feces, whereas absorbed serum
biotin is excreted through the kidney.22 In addition to
malabsorptive diseases and alcohol use disorder, deficiency
can occur in patients with biotinidase deficiency, individuals
consuming large amounts of raw egg whites, and pregnant
and lactating women.19 Deficiency of biotin can manifest as
alopecia (Figure 6), brittle nails (Figure 7), and dermatitis,
DiBaise and Tarleton
Figure 7. Brittle nails. Photo courtesy of ALAIN
VERMEULEN Adobe Stock images.
particularly involving the face.19 Patients may also experi-
ence myalgias, paresthesias, and mental status changes.19
Testing for deficiency is best assessed through measure-
ment of white blood cell biotinylated methylcrotonyl CoA
carboxylase and propionyl-CoA carboxylase. Alternatively,
biotin levels in serum and urine can be measured.19 There
are no set recommendations for biotin supplementation,
and dosage and duration of supplementation vary.21 Due
to the lack of data, there is no UL for biotin, nor is
there an RDA; instead, the recommendations are provided
as adequate intake (AI).11,13 The AI is 30 µg daily for
adults, and a typical varied diet generally provides sufficient
amounts of biotin. Many people supplement their diets with
additional biotin up to 500–1000 µg/d.21 High doses of
biotin, however, may cause falsely elevated thyroxine and
triiodothyronine levels, mimicking Grave’s disease23,24 or a
falsely low troponin level.25
Vitamin B12
Dietary sources substantial in vitamin B12 include animal
products, particularly meat, fish, dairy products, and eggs,
but B12 is also present in fortified cereals.6,26 The RDA for
vitamin B12 is 2.4 µg/d for adult men and nonpregnant
women with no UL, as it is not determinable.11,13 Vitamin
B12 bound to protein requires release through the action
of gastric acid and proteases, but this step is not necessary
when vitamin B12 is in the form of supplements or fortified
cereals.26 Vitamin B12 is absorbed in the distal ileum after
binding with intrinsic factor (IF), a protein secreted by
the parietal cells of the stomach. Deficiency can occur in
patients with achlorhydria, atrophic gastritis, celiac disease,
or Crohn’s disease; after bariatric surgery or resection
of the distal ileum; patients on metformin (>4 months);
use of proton pump inhibitors or histamine H2 blockers
(>12 months); adults older than 75 years; and in vegans
or strict vegetarians, particularly those who are pregnant
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.
Deficiency 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 deficiency
may initially present with glossitis and not show signs of
anemia early on.28 Testing for deficiency is best assessed
through serum or plasma vitamin B12 levels.26 Levels <170–
250 pg/mL are consistent with vitamin B12 deficiency.26
An alternative test is methylmalonic acid (MMA), in which
an elevated level (>0.4 µmol/L) indicates vitamin B12
deficiency.26
Treatment of vitamin B12 deficiency is imperative,
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
high-dose oral supplements (1000–2000 µg daily), 1%–2%
of vitamin B12 is absorbed through passive diffusion in an
IF-independent process and is enough to meet the daily
need.29 Nevertheless, there continues to be uncertainty of
oral vitamin B12 supplementation in deficiency, as it may
not improve serum MMA levels, as well as intramuscular
(IM) or subcutaneous therapy.27 The American Society of
Hematology does not have specific guidelines on oral vs
IM injections for vitamin B12 replacement, except in the
presence of neurologic impairment.30 The British Society
for Haematology recommends vitamin B12 IM injections
for severe deficiency and in patients with malabsorption
and to reserve oral supplementation for patients who are
compliant, asymptomatic, and have normal absorption with
mild deficiency.27 A common dose for repletion in deficient
adults is 1000 µg cyanocobalamin IM injection once per
week until the deficiency is corrected.31 Recommendations
for IM injections for treatment of pernicious anemia range
from 100 to 1000 µg cyanocobalamin for 5 days and then
100–1000 µg on a monthly basis.31 Vegans and strict vege-
tarians should be intentionally consuming fortified cereals
on a regular basis and/or take a vitamin B12 supplement.27
Ascorbic Acid (Vitamin C)
Dietary sources rich in vitamin C include citrus fruits, a
variety of peppers, tomato sauce, fortified juices, broccoli,
spinach, strawberries, and potatoes.6 Vitamin C is absorbed
in the distal small intestine and excreted by the kidneys.32
Vitamin C is necessary for collagen synthesis.1,32,33 In ad-
dition to malabsorptive diseases and alcohol use disorder,
deficiency can occur in both tobacco smokers and individ-
uals exposed to second hand smoke, in infants fed predom-
inantly evaporated or boiled cow’s milk, in patients with
iron overload such as from hemolysis, and in patients with
end-stage renal disease on hemodialysis.1,32,33 Deficiency
496
Figure 8. Gingival inflammation with tooth loss seen in
scurvy. Image is from page 285 of Modern surgery, general and
operative (1919) (no known copyright restrictions).
Figure 9. Follicular-based petechiae with corkscrew hairs seen
in scurvy. Photo courtesy of DermNet New Zealand.
of vitamin C can manifest as scurvy with fatigue, gingival
inflammation (Figure 8), follicular-based petechiae with
corkscrew hairs (Figure 9), poor wound healing, joint pain,
and thickening of the skin (hyperkeratosis).1,32,33 Patients
may also experience tooth loss, depression, bone disease,
and iron deficiency anemia from bleeding.1,32,33
Testing for deficiency is best assessed through measure-
ment of serum or leukocyte vitamin C levels.1,32,33 In healthy
individuals, the RDA for vitamin C is 90 mg/d for men and
75 mg/d for women with the UL being 2000 mg daily for
both adult men and women.11,13 Replenishment of vitamin
C deficiency may require up to 300 mg daily in pediatrics
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 sufficient 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
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
absorbed in the small intestine with the aid of pancreatic en-
zymes and bile salts. Deficiency can occur with maldigestive
and malabsorptive disorders, pancreatic insufficiency, 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 Deficiency will manifest as impaired night vision
and xerophthalmia.1,2,40 Over time, severe deficiency can
lead to complete blindness. In addition to visual problems,
deficiency 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 deficiencies of the B
vitamins, vitamin E, EFAs, and general malnutrition.41,42
Testing for vitamin A deficiency is best accomplished
through measurement of plasma retinol and carotenoid
levels.40 The RDA for vitamin A for adult males is 3000 IU
(900 µg retinol) daily and for females 2300 IU (700 µg
retinol) daily.6,43 There are no set guidelines for treating
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
Organization recommendation for the treatment of vitamin
A deficiency with xerophthalmia includes immediate use
of oil-based oral vitamin A of 200,000 IU, with a repeat
dose on days 2 and 14. Subsequent supplementation with
doses of 200,000 IU is recommended every 4–6 months.45
Water-miscible vitamin A is an alternative form used in
individuals with fat malabsorption disorders.46 The UL for
vitamin A is 10,000 IU (3000 µg) daily for adult men and
10,000 IU (3000 µg) daily for nonpregnant adult women.43
Acute vitamin A toxicity can occur in adults with a dose
of >660,000 IU (>200 mg).47 Chronic toxicity can occur
with long-term ingestion of high-dose vitamin A. Vitamin
DiBaise and Tarleton
Figure 10. Petechiae can be associated with vitamin K and
less commonly vitamin E deficiencies. Photo courtesy of
drpilulkin Adobe Stock images.
A is potentially teratogenic during the first trimester of
pregnancy at doses above the RDA.47
α-Tocopherol (Vitamin E)
Vitamin E is commonly found in nuts, green leafy veg-
etables, fortified cereals, and vegetable oils.48 Vitamin E is
absorbed in the small intestine and, like vitamin A, is fat
soluble and requires pancreatic enzymes and bile salts for
absorption, transport, and storage in the liver. In addition
to malabsorptive disorders, pancreatic insufficiency, severe
cholestatic diseases, and with medication use that interferes
with fat absorption, deficiency can occur in both tobacco
smokers and individuals exposed to second hand smoke.48
A deficiency of vitamin E has been associated with the
development of lipofuscin, a ceroid pigment that can lead to
brown deposits in tissues, specifically bowel, muscle tissue,
and the retina.48 In addition to ceroid pigment deposits,
patients with vitamin E deficiency can develop hemolysis
with petechiae (Figure 10), ataxia, and other neuropathies.48
Testing for deficiency is best accomplished through mea-
surement of serum α-tocopherol levels when serum lipid
levels are normal. In hyperlipidemia, the α-tocopherol level
must be divided by the total lipids (cholesterol + triglyc-
erides). A value >0.8 mg is considered normal.48 The RDA
for vitamin E in adults is 15 mg/d of dietary α-tocopherol
with the UL being 1000 mg/d.11,13 Therapeutic replacement
dosing of vitamin E is not well defined. In adults, treatment
with oral vitamin E ranges from 200 to 2000 mg/d.49 Water-
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
There are mixed data about consuming high doses of
vitamin E (>1200 mg/d) and the risk of competition with vi-
tamin K, increased bleeding for patients receiving warfarin,
and a decrease in platelet adhesion.49,53,54 Caution is recom-
497
mended when using high-dose vitamin E supplementation,
as there have been studies to suggest an increase in all-cause
mortality.51,52
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
Vitamin K is also a cofactor in osteocalcin, important in
bone mineralization.55 In addition to malabsorptive dis-
orders, pancreatic insufficiency, severe cholestatic diseases,
and medication use that interferes with fat absorption,
deficiency of vitamin K has been associated with newborns
not receiving vitamin K at birth, use of warfarin (or sim-
ilar anticoagulants), and antibiotic use which can destroy
gut bacteria that produce vitamin K.55,56 Bleeding is the
typical clinical presentation in vitamin K deficiency. Pe-
techiae and purpura are common cutaneous manifestations
(Figure 10).
Testing for deficiency is best assessed through measure-
ment of prothrombin time (PT)/international normalized
ratio (INR), as mild deficiency will affect Factor VII
first.55,56 In severe deficiency, both PT and partial thrombo-
plastin time can be affected. In this instance, measurement
of vitamin K–dependent proteins (Factor II [prothrombin],
VII, IX, X, and/or protein C) will guide the diagnosis.55,56
The AI for vitamin K in men is 120 µg and in women
is 90 µg/d; the UL is not determinable.11,13 There are no
standard guidelines for treating vitamin K deficiency, but
supplementation regimens range from 2.5 to 10 mg, twice
weekly to daily with oral or injected forms. Because the
amount of vitamin K in lipid injectable form varies depend-
ing on the composition in the manufacturing process, care
should be taken to monitor dosing with injectable forms.56
It is important to remember that warfarin and vitamin K
are antagonists; therefore, once the goal INR is met, daily
vitamin K intake should remain consistent. An increase in
vitamin K intake without adjustment of warfarin may lead
to an increased risk of clotting.53
Minerals
Zinc
Dietary sources rich in zinc include beef, fish, oysters, liver,
beans, and soybeans.6 Zinc is also present in over-the-
counter cold lozenges and denture adhesive.57 The RDA for
zinc is 11 mg daily for adult men and 8 mg daily for non-
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 deficiency,
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 defi-
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 deficiency due to an autosomal recessive
disorder affecting zinc absorption presents in infancy with
acrodermatitis enteropathica.1,57 Zinc deficiency, whether Figure 12. Perianal dermatitis associated with zinc deficiency
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 deficiency affects the perioral, per-
ineal, and acral areas with a vesicular or pustular rash
(Figures 11–13).1,2,57
Testing for deficiency is best assessed through
measurement of plasma or serum zinc levels; however, these
tests are not always accurate in measuring deficiency.1,57 It
is recommended that clinical correlation with laboratory
results and presence of risk factors assist in the
diagnosis.
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 deficiency
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.
Iron
Heme iron is commonly found in meat, poultry, and fish,
and non-heme iron is found in vegetables, fruits, and forti-
fied 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 deficiency can be found
Figure 11. Perioral dermatitis associated with zinc deficiency. 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
Figure 14. Koilonychia associated with iron-deficiency anemia
Photo courtesy of CHeitz (Flickr).
with malignancies, particularly colon cancer; in patients
who have had GI surgeries; and patients with chronic
heart failure.60 Iron deficiency can lead to a microcytic,
hypochromic anemia with associated pallor along with fa-
tigue, exertional dyspnea, koilonychia (spoon-shaped nails)
(Figure 14), and developmental delays in children.60
Deficiency is generally considered in the setting of mi-
crocytic, hypochromic anemia determined by a complete
blood count.60 This is, however, not specific for iron defi-
ciency, whereas iron studies that may include serum iron
level, total iron binding capacity, transferrin, serum ferritin,
and transferrin saturation will allow for a more specific
diagnosis of iron deficiency.60 With inflammatory reactions
(acute-phase reaction), transferrin and serum iron levels
may decrease, whereas serum ferritin levels may increase.
This contradictory pattern of lab findings should lead
the provider to investigate for an underlying inflammatory
process or infection.
Oral iron supplementation is generally considered first
in the treatment of iron deficiency. Iron sulfate is most
frequently used; however, iron gluconate and iron fumarate
are also good alternatives. Recommended dosing for adults
is 100–200 mg of elemental iron.61 Divided doses in between
meals with a vitamin C source will optimize absorption.
Repletion of iron stores and normalization of serum ferritin
will typically occur within 3–6 months of treatment. Adher-
ence to treatment may be compromised by side effects such
as nausea, vomiting, constipation, and a metallic taste. If
treatment with oral iron fails, including premature termi-
nation of treatment, lack of adequate adherence with the
regimen, or a refractory response to treatment, parenteral
iron should be initiated.61
There are 5 forms of parenteral iron available in
the United States: INFeD (iron dextran), Venofer (iron
sucrose), Injectafer (ferric carboxymaltose), Ferrlecit
499
Figure 15. Kayser-Fleischer rings associated with Wilson’s
disease Photo courtesy of Herbert L. Fred, MD, Hendrik A.
van Dijk Wikimedia.
(sodium ferric gluconate), and Feraheme (ferumoxytol).
Hypersensitivity reactions can occur with any of these
preparations; therefore, they should be administered where
the patient can be closely monitored with resuscitation
equipment and personnel trained to respond to an
anaphylactic reaction.62-66 There is currently no form of
parenteral iron that is suitable for addition to PN in the U.S.
Copper
Beef, soy, nuts, seeds, beans, shellfish, and mushrooms
are all good sources of dietary copper.6 The RDA for
copper is 900 µg/d for adult men and for nonpregnant
adult women, with the UL being 10,000 µg/d.58,59 Copper
is absorbed in the stomach and proximal small intestine
and is decreased in the presence of iron, zinc, and vita-
min C.67 Copper is transported to the liver where it is
bound to ceruloplasmin for transport to tissues.67 Copper
is eliminated in the GI tract, predominantly in bile. Copper
deficiency can be found in patients who have undergone
gastric bypass or gastrectomy, premature infants on milk
formulas without copper, in patients with chronic excess zinc
ingestion, and in patients overtreated for Wilson’s disease.68
Wilson’s disease is a deficiency in ceruloplasmin leading to
excessive copper deposits in multiple organs. Classic signs
are azure lunula and Kayser-Fleischer rings of the eyes
(Figure 15).69 A rare X-linked disorder, Menkes disease,
results in copper deficiency due to inability to absorb copper
from the intestine. Copper deficiency leads to abnormally
formed hair (kinky hair syndrome) (Figure 16), skin de-
pigmentation (Figure 17), ataxia, myeloneuropathy, and
hepatosplenomegaly.70 The signs and symptoms of Menkes
disease are similar to acquired copper deficiency, except
Menkes is more severe and diagnosed early in infancy with
associated developmental delay, epilepsy, and progressive
neurologic symptoms.70
Testing for deficiency is accomplished by measurement
of serum copper and ceruloplasmin levels; however, like
500
Figure 16. Kinky-hair syndrome associated with Menkes
disease Photo courtesy of Datta AK, Ghosh T, Nayak K,
Ghosh M. Menkes kinky hair disease: A case report. Cases J.
1, 1, 158. 2008. https://doi.org/10.1186/1757-1626-1-158.
(Wikimedia).
Figure 17. Skin depigmentation associated with copper
deficiency Photo courtesy of 
C A. Bueckert Adobe Stock
images.
ferritin, both are also acute-phase reactants and can be
elevated in the presence of inflammatory processes.69,70
Treatment of Wilson’s disease consists of avoidance of
high-copper foods and copper chelation.69 In early stages,
high doses of zinc may be effective in delaying the onset
of symptomatic disease, as zinc competes with copper for
absorption in the GI tract. Copper can be administered
orally or intravenously for deficiency; however, there are no
set recommendations regarding dose, route, or monitoring
parameters.71,72 The American Society for Metabolic and
Nutrition in Clinical Practice 34(4)
Figure 18. Whitened nail beds associated with selenium
deficiency. 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
Recommendations for copper supplementation for mild-to-
moderate deficiency are oral copper 3–8 mg/d until levels
are corrected and, in the setting of severe symptomatic
deficiency, 2–4 mg/d of intravenous copper for 6 days
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
Selenium
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 µg/d for adult men and nonpregnant women, with
the UL being 400 µg/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,
deficiency is more common. This is particularly true for veg-
etarians living in selenium-deficient areas.74 Deficiency may
also occur in patients on long-term hemodialysis; receiving
long-term PN; having chylous loss, phenylketonuria, or
malabsorption disorders; and in individuals with HIV.74-77
Selenium deficiency leads to whitened nailbeds (Figure 18),
impaired immune function, and skeletal myopathy. Patients
receiving long-term PN without selenium supplementation
may develop cardiomyopathy.76
Testing for deficiency is generally accomplished through
measurement of serum or plasma selenium levels, although
selenium levels in hair and nails can provide a more accurate
long-term assessment of intake. The optimal dose and dura-
tion of selenium supplementation is not well established.77
DiBaise and Tarleton
Figure 19. Desquamation associated with deficiency of
essential fatty acids. Photo courtesy of nataba Adobe Stock
images.
A common dose of oral selenium for adults is 100 µg/d.78
The amount of selenium in multi-trace element (MTE)
formulations for PN vary by age group (neonate, pediatric,
and adult). The standard amount of selenium that is present
in MTE-5 for adults is 60 µg, whereas the recommended
amount for neonates and pediatric populations is based
on weight. Importantly, the MTE-4 formulation does not
contain selenium.39
EFA Deficiency (Linoleic and α-Linolenic
Acids)
Linoleic acid and α-linolenic acid cannot be synthesized
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 safflower.3 EFAs are absorbed
in the distal jejunum and ileum, then packaged and trans-
ported to the liver, muscle, and adipose tissue.3 In addition
to malabsorptive disorders, pancreatic insufficiency, severe
cholestatic diseases, and with medication use that interferes
with fat absorption, EFA deficiency can occur in patients
with resection of the distal jejunum and ileum or following
bariatric surgery, in patients with marked restriction of fat in
their diet, and in patients on long-term PN who are unable
to receive intravenous fat emulsion.3 Deficiency of EFAs
leads to desquamation (Figure 19) and dermatitis, alopecia,
poor growth in infants and children, poor wound healing,
and thrombocytopenia.3
Testing for deficiency is accomplished by measurement
of the serum triene-tetraene ratio.3 In the absence of linoleic
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
ratio (>0.2) is indicative of EFA deficiency.3 EFA deficiency
can be prevented in the PN population by providing at
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 deficiency with higher doses needed in patients
with preexisting deficiency.3 In patients with pancreatic
insufficiency, appropriate pancreatic enzyme replacement is
essential to ensure that EFA replacement will not worsen fat
malabsorption.3
Conclusion
Although MNDs are uncommon in the general population,
a number of conditions are at risk of these deficiencies,
including those patients with restricted diets; chronic med-
ical disorders including malabsorptive conditions, pancre-
atic insufficiency, or end-stage renal disease; and use of
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
products including micronutrients may also contribute to
deficiencies.81 Shortages require thorough communication
and a team approach to care. In this setting, oral and enteral
routes of therapy should be attempted whenever possible,
reserving parenteral multivitamin and trace elements for
those who are entirely PN dependent.82
MNDs frequently lead to abnormalities of the skin, hair,
and nails, which can serve as early warning signs for defi-
ciency. An awareness of these changes allows the healthcare
provider to intervene with confirmation of the diagnosis
and implementation of adequate supplementation as well
as identification and treatment of the underlying disorder
causing the deficiency.
Statement of Authorship
M. DiBaise and S. M. Tarleton equally contributed to the
conception and design of the work; M. DiBaise and S. M.
Tarleton contributed to the design of the manuscript; M.
DiBaise and S. M. Tarleton contributed to the acquisition
and analysis of the data; M. DiBaise and S. M. Tarleton
contributed to the interpretation of the data; and M.
DiBaise and S. M. Tarleton drafted the manuscript. All
authors critically revised the manuscript, agree to be fully
accountable for ensuring the integrity and accuracy of the
work, and read and approved the final manuscript.
Supplementary Information
Additional supporting information may be found online in the
Supporting Information section at the end of the article.
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