Introduction:

Zinc is
a trace element essential to countless metabolic pathways and cellular
functions of the body. It is involved in protein and nucleic acid synthesis,
and plays a role in immune function, wound healing, DNA synthesis and cell division.(1,2)
Due to the importance of these functions a deficiency of zinc poses a major
health problem worldwide.(3) Zinc deficiency can
occur from a lack of adequate dietary intake, decreased intestinal absorption,
and increased losses in the gastrointestinal tract, urine, and sweat.(4)
Zinc deficiency has been noted to occur in patients with
malabsorption syndromes, chronic renal disease, cirrhosis of the liver, sickle
cell disease, and in patients with malnutrition, alcoholism, and inflammatory
bowel disease.(5)

The skin
has the third highest abundance of zinc in the body. The epidermis
has a higher concentration than the dermis, owing to
a zinc requirement for the active proliferation and differentiation
of epidermal keratinocytes.(6) Zinc inhibits hair follicle
regression, and helps accelerate hair follicle recovery.(7)
Cutaneous manifestations typically occur in moderate to severe
zinc deficiency and present as alopecia and dermatitis in
the perioral, acral, and perineal regions.(8)

Studies
arguing that zinc deficiency can negatively affect the growth of hair in adults
have been emerging since the 1990s, with even a few studies having reported
that zinc deficiency has correlations with alopecia areata and telogen
effluvium.(9) Little is known about zinc deficiency and hair loss in
the pediatric population in comparison to adults. In 1985 Collipp, P J, et al.
investigated the association between zinc levels in the hair of normal infants with
scalp hair quantity and the presence of a diaper rash. The study
indicated that hair loss and diaper rash in normal infants are
significantly associated with a reduction in hair zinc concentration.(10)
Another case reported progressive diffuse hair
loss with hair dryness and brittleness due to dietary zinc
deficiency.(11) However, serum zinc levels association with hair
loss has not been well studied in the pediatric population. Therefore, the aim
of this study is to assess serum zinc levels in children with hair loss and to
find characteristics that predict particularly low zinc levels.

Materials and methods:

Patient
population:

This was
an out-patient clinic based prospective observational study done in pediatric
and dermatology clinics in Al-Karak teaching hospital affiliated with Mutah
University, Jordan. The ethical committee approved the study protocol. Informed
consent from the patients’ parents was obtained prior to enrolment in the
study.

A
protocol was developed and implemented to collect the data of all pediatric
patients who were seen at the dermatology and pediatric clinics during January
2014 to January 2017. All patients who were complaining of hair loss (partial
or diffuse), change in hair texture or regression of hair growth, or who were
found to have hair loss or scalp disorders on physical examination, and
confirmed to have low zinc levels were included in this study. Patients with
normal hair, normal serum zinc levels, or were taking multivitamin
supplementations were excluded from the study. The total number of patients
screened was 5200 (2800 in dermatology clinics and 2400 in pediatric clinics).

History
taking and physical exam methodology:

A
detailed history was taken regarding hair symptoms including; the type of hair
loss (partial or diffuse), scalp symptoms, changes in hair texture and the
growth of hair. In addition, history of any hair changes in other parts of the
body including the eyebrows or eyelashes was taken. The data collected included
age, sex, and clinical presentations. The way patients presented themselves to
their physician was classified into three groups. Group 1 was defined as those
who complained of hair loss as their primary concern, group 2 was defined as
those who complained of hair loss as a secondary concern alongside another more
significant concern to them, and group 3 was defined as those who did not
complain of hair loss. In addition, detailed history was taken about hair
grooming/habit tics, nail changes, other cutaneous changes, systemic diseases
(e.g. cystic fibrosis, celiac disease, cow milk allergy, and enteritis), family
history of similar conditions or autoimmune disease, and drug history. Economic
status was assessed by the family income per capita, and was classified
according to the World Bank new data on July 1, 2017, as high, upper-middle,
lower-middle, or low income. Diatery history focused on piky eaters who
excludes animal

products (ie, meat, poultry, and fish) and having lower
diversity of food. Early-onset picky eating was defined as the first report of
picky eating being at either 2 or 3 y, and late-onset picky eating was defined
as the first report of picky eating being at 4.5 or 5.5 y, Persistent picky
eating was defined as being in the early-onset group and persist.(12).{ Macro- and micronutrient intakes in picky
eaters}

Scalp
examination included the skin of the scalp (presence of erythema, scales, and
follicular plugging). Hair examination included the recording of hair color,
texture, fragility, and examination of the hair root. In addition to the scalp,
other hairy sites were examined for hair loss (including eyebrows and eyelashes).
Nails and teeth were also examined for any abnormalities.

Anthropometric
measures assessed included weight for height, height for age, and weight for
age. The values for each nutritional index were converted into Z scores
(Standard deviations) according to the 2000 CDC.(13)
growth charts. Z scores between +1 and -1 were considered normal, between -1
and -2 low, and below -2 very low.

Biochemical
methodology:

Total
zinc concentration in the patients’ serum was measured using an automated
chemistry analyzer (Biosystem BT-350 module, Spain) according to the
manufacturer protocol, low zinc level was defined by serum zinc less than 70
µg/dL. Hemoglobin, ferritin, and vitamin D levels were also obtained to assess
nutritional status. Anemia was defined as a hemoglobin level less than 11 g/dL.
Ferritin was considered to be deficient when
below 12 ng/mL for children less than 5 years of age and below 15 ng/mL for
those above 5 years. Vitamin D was considered to be deficient when below 25
nmol/L (World Health Organization 2001).
(14)

Other
investigations carried out included sweat chloride test for cystic fibrosis, as
well as Tissue Transglutaminase antibody IgA to screen for celiac disease.
These tests were performed in some cases to further confirm the presence of
systemic diseases. Blood tests for thyroid function, antinuclear antibody, and other
auto antibodies were also performed where necessary in
some cases.

Statistical
methodology:

In this
study four main statistical tests were used. Namely, the independent Student’s
T-test, the ANOVA, the Pearson Chi-Square test, and the Fisher exact test. The Student’s
T-test and the ANOVA were used to analyze the mean zinc levels. The Chi-Square
test was used to find an association between two categorical variables. The Fisher
exact test was used when a Chi-Square test was not a viable option.

The
tolerated maximum probability of a type 1 error in this study was 0.05 (i.e. ?
= 0.05). Any P-value below 0.05 is considered to be statistically significant. SPSS
V. 21.0 software was used for the statistical analysis.

Results:

Mention
ANOVA/T-Test

Of the
5200 cases screened, 401 cases had hair loss. Of those with hair loss 162 had
zinc deficiency. Therefore, the prevalence of zinc deficiency in this pediatric
population with hair loss was 40.4%. Figure x
demonstrates the distribution of patients seen in detail.

Among
the 162 patients analyzed in this study, 61% were female and 39% male. The age
ranged from 1 month to 14 years with a mean of 4.8 ± 3.1 years. When categorizing the patients based on how they
presented to the physician 21.6% were within group 1, 32.1% were within group
2, and 46.3% were within group 3. On physical examination 31.5% had diffuse
hair loss, 14.2% had patchy hair loss, 58% had a scaly scalp, 95.1% had hair
texture or color changes, and 30.2% had other skin manifestations.

7.4% had
an underlying systemic illness. 51.5% had no family history of hair loss. 10.5%
had a family history pertaining to the mother only, 25.9% to a sibling, and
12.3% the mother and a sibling. According to the World Bank organization
classification 4.9% had a low household income, 59.9% had a lower-middle
household income, 33.3% had an upper-middle household income, and 1.9% had a
high household income. 42.6% had a low or very low weight to age z score, 29%
had a low or very low height to age z score, 48.8% had a low or very low weight
to height z score.

The mean
zinc level was 51.3 ± 11.2 ?g/dL. Table 1 summarizes the factors associated
with differences in mean zinc levels. There was no statistically significant
difference between the mean zinc level in males and females, or between the age
groups. Although the sex of the patient had no significant association with
zinc levels when looking at the patient sample overall, when looking only at
patients who complained primarily of hair loss (i.e. Group 1), it was found
that males had a significantly lower mean zinc level than females. Furthermore,
females were almost 5 times more likely to complain primarily of hair loss than
males (P<0.001). Ferritin deficiency was not associated with a lower mean zinc level. However, both anemic and vitamin D deficient patients were associated with a lower mean zinc level than normal patients. Interestingly, the presence or absence of either anemia or vitamin D deficiency was not correlated with how the patient presented themselves to the physician with hair loss (P=0.140 for anemia, and P=0.584 for vitamin D). Patients who were aware of their hair loss (Groups 1 and 2) had a significantly lower mean zinc level than patients who were not (group 3). The presence of diffuse hair loss, patchy hair loss, a scaly scalp, hair texture or color changes, or skin manifestations were all associated with a lower mean zinc level. Patients with lower weight for age z scores, height for age z scores, and weight for height z scores were associated with a lower mean zinc level. The presence of a family history of hair loss associated with a decreased mean zinc level. Furthermore, there was no major difference between mean zinc levels in the four different family income categories. The majority of this study population (92.6%) did not have any systemic diseases and their dietary problems are the leading cause of zinc deficiency and their hair loss. Of the 162 patients in this study, 137 have been grouped based on their diet. The other 25 were too young to be classified 24.1% of those that were grouped were early picky eaters, 32.1% were late picky eaters, 16.8% were persistent picky eaters and 27% were never picky eaters. Persistent picky eaters had the lowest zinc level (38.7 ?g/dL), followed by early picky eaters (46.0 ?g/dL), late picky eaters (55.4 ?g/dL), and then finally those who were never picky eaters (61.8 ?g/dL) (P<0.001, F=65.4). On other hand,7.4% had an underlying systemic illness, there was a statistically significant difference between the mean levels of those who had an underlying illness and those who did not (36.6 and 52.5 ?g/dL respectively, P<0.001, T=5.1). Therefore, the presence of an underlying systemic disease was associated with a decreased mean zinc level. On other hand, we had only 13cases(7.4%) had systemic diseases, 11cases  had risk factors of zinc deficiency and presented with hair loss beside their major complications. Among them three case have celiac disease mean zinc level (31.6 ?g/dL), three case of cystic fibrosis (27?g/dL), four patients with cow milk allergy (31.6 ?g/dL), a patient know to have congenital hypotherodism and another patient reported to have hereditary acrodermatitis enteropathica .     Discussion: Zinc can be a cofactor for almost every known subtype of human enzyme, hence its deficiency has a very wide range of presentations, which can cause a delay in diagnosis and lead to progression to a more severe and dangerous deficiency.(1,5) Untreated severe zinc deficiency can be a potentially fatal disease process(5,15) .The manifestations of severe zinc deficiency include bullous pustular dermatitis, alopecia, diarrhea, emotional disorders, weight loss, recurrent infections, hypogonadism in males, neurosensory disorders, and problems with the healing of ulcers.(15) Being able to recognize a likely case of zinc deficiency and estimate the severity of this deficiency using mainly clinical information can be invaluable in avoiding many more complications. The prevalence of zinc was high in pediatric patients with hair loss (40.4%), indicating that zinc deficiency is not only an important cause of hair loss in adults, but is a problem in children as well and should be considered as part of the differential diagnosis. In this study it was found that if patients were aware of their hair loss and complain about it (either as a primary complaint or a secondary complaint), they are more likely to have a lower zinc level than those who were only found to have hair loss on physical examination. Patchy hair loss seems to be the sign with the lowest associated zinc level. Diffuse hair loss, hair texture and color changes, a scaly scalp, and skin manifestations also predict low zinc levels. The presence of anemia or vitamin D deficiency lowered the likely mean zinc level to be found. This could mean that the presence of anemia and vitamin D deficiency are hints towards a nutritional defect that also happens to cause zinc deficiency. Interestingly, although iron nutritional sources overlap significantly with zinc sources (16, 17) Need Source, low ferritin did not have a statistically significant correlation with lower zinc levels. This was probably due to a small number of patients in this study who did not have ferritin deficiency; a larger sample size would be useful to reach a conclusion regarding ferritin. Of note, neither anemic patients nor vitamin D deficient patients had an increased likelihood to present with hair loss as a primary complaint. Both sex and age were poor predictors of zinc levels when looking at the whole patient sample. However, it seems that when males complain of hair loss primarily they have a much more severe zinc deficiency than their female counterparts who have the same complaint. Females were almost 5 times more likely to complain of hair loss as their primary complaint than males. One possible explanation could be that parents have a higher cosmetic concern for females, and so males present later with a more severe deficiency as well as other non-hair related symptoms. Height-for-age is an important functional indicator that can help establish the nutritional status of zinc deficiency (18), in this study population  A low or very low weight for age z score, height for age z score, weight for height z score, all predicted lower serum zinc levels than people with normal z scores. The presence of a family history or an underlying illness also predicted lower serum zinc levels. The family income of the patient did not predict serum zinc levels.   Dietary inadequacies may arise from low zinc intakes per se or poor absorption of dietary zinc(19).In low-income countries where diets are predominantly plant-based foods, especially cereals, are high in phytate, which inhibits the absorption of zinc, young children are at greatest risk of zinc deficiency and may be exacerbated by a physiologic state with higher zinc requirements due to their growth(20).Because there is no functional reserve or body store of available zinc, except possibly in infants(21),  adequate dietary supply is required. Most of the patient in this study (92.6%) had hair loss due to zinc deficiency resulting from poor diet consumption with higher mean zinc level comparing to underlying illnesses (52.5 and 36.6 ?g/dL respectively, P<0.001, T=5.1 52.5), and their hair loss was less sever and progress slowly.This provides the conclusion that mild to moderate zinc deficiency is common in low-resource settings. Reductions in the consumption of whole-grain products, fish and seafood, meat, and unsweetened cereals and increases in savory snacks and confectionary cereals and French fries in picky eaters compared with nonpicky eaters have also been noted(22,23). Based on this fact, we can argue that such low diversity of food in picky eaters can increase the risk of zinc deficiency which may be attributed to their hair loss. In this study persistent picky eaters had the lowest zinc level (38.7 ?g/dL) among all type of picky eaters. Moreover, the picky eater behavior was likely associated with how a patient presents (?2 = 21.71, P=0.001), Patients who were never picky eaters were less likely to complain of hair loss (group 1 and 2), in comparison to patients who had some sort of picky eating. Persistent picky eating especially was the most likely to have hair loss complaints on presentation.   Acrodermatitis enteropathica  is the prototype of the severest forms of human zinc deficiency, with total body zinc is not greatly reduced, but the plasma zinc concentrations are typically extremely low (e.g. <30 ?g/dl(24).This is an examples of genetic hair disorders caused by nutritional zinc deficiency(25). Other examples of poor absorption of dietary zinc are celiac disease and cystic fibrosis.  The presentation of infants and young children with celiac disease overlaps with several of the features of zinc deficiency: anorexia, diarrhea, and short stature (25, 26). Zinc deficiency has been documented in young infants identified by newborn screening prior to initiation of pancreatic enzyme therapy. (26, 27)In settings without newborn screening, presentation is typically later in infancy, with associated growth faltering, diarrhea, and dermatitis similar to Acrodermatitis enteropathica. (27,28) the hypozinemia in these two diseases may be attribuated to patients hair loss. New finding in this study was the presentation of  hair loss in patients with cow milk allergy, we may argue that hypozinemia due to chronic enteritis may augment hair loss beside their skin manifestation. In this study, systemic causes were less common as a cause of hair loss (7.4%).However, their symptoms were more obvious particularly their alopecia, and their zinc deficiency more sever (serum zinc mean was36.6  ?g/dL ).  Interestingly, the most severely affected patient was a two moths tiny baby with acrodermatitis enteropathica complicated with sever failure to thrive and hair loss include almost the whole scalp and his serum zinc level was 25 micg/dl , The skin lesions and alopecia disappeared when serum zinc values were raised to levels above 60 micrograms/dL, and She had a positive clinical evolution after Zinc supplementation.     Hypothyroidism is a well-known cause of hair loss. However, zinc and other trace elements are required for the synthesis of thyroid hormones, and so zinc deficiency can result in hypothyroidism, which can be masked in children. Furthermore, hypothyroidism can result in further zinc deficiency as thyroid hormones are essential for the absorption of zinc. Zinc supplements have been shown to improve hair loss attributed to hypothyroidism. (29) All the patient with zinc deficiency were started on zinc supplementation in a dose of (0.5-1mg) per day for 3-6 months, in addition to modification of their diets. The hair loss stopped in 6-8weeks ,  Follow up in next few months showed no evidence of alopecia , with normal looking hair ,  Except the case caused by hereditary acrodermatitis enteropathica and the patients with cystic fibrosis who were severely affected and needed higher dose and longer duration of treatment.   It has been reported that severe zinc deficiency associated with a severe type of hair loss was treated with zinc supplementation (50 mg daily) for 6 months as well as improving the patient's diet.(11) In this study similar findings were also found, however, in patients with underlying disorders zinc supplements were not as effective and needed to be used for a longer time before any improvement was noticed. Interestingly, there is some evidence to support that blind treatment with zinc supplements for hair loss without documenting the actual low level of zinc may exacerbate the hair loss and are not recommended in the absence of a proven deficiency. (30) .   In summary, there are many predictive factors for the severity of zinc deficiency in pediatric patients with hair related symptoms or signs. Patchy hair loss , very low body weight for age , persistent picky eaters and the presence of an underlying illness such as celiac disease and cystic fibrosis seem to be the four characteristics associated with the lowest mean zinc levels. Further studies to examine the usefulness of the clinical assessment of hair loss and skin manifestations to directly predict zinc deficiency related complications such as recurrent infections would be extremely useful to clinicians.