Introduction: University, Jordan. The ethical committee approved the

Introduction:Zinc isa trace element essential to countless metabolic pathways and cellularfunctions of the body.

It is involved in protein and nucleic acid synthesis, italso 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 majorhealth problem worldwide.(3) Zinc deficiency canoccur from a lack of adequate dietary intake, decreased intestinal absorption, aswell as increased losses in the gastrointestinal tract, urine, and sweat.

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(4)Zinc deficiency has been noted to occur in patients withmalabsorption syndromes, chronic renal disease, cirrhosis of the liver, sicklecell disease, and in patients with malnutrition, alcoholism, and inflammatorybowel disease.(5)The skinhas the third highest abundance of zinc of any organ in the body. Theepidermis has a higher concentration of zinc than the dermis, owing toa zinc requirement for the active proliferation and differentiationof epidermal keratinocytes.(6) Zinc has been shown to inhibit hairfollicle regression, and help in accelerating hair follicle recovery.

(7)Cutaneous manifestations typically occur in moderate to severezinc deficiency and present as alopecia and dermatitis inthe perioral, acral, and perineal regions.(8)Studiesarguing that zinc deficiency can negatively affect the growth of hair in adultshave been emerging since the 1990s, with even a few studies having reportedthat zinc deficiency has correlations with alopecia areata and telogeneffluvium.(9) Little is known about zinc deficiency and hair loss inchildren in contrast to adults. In 1985 Collipp, P J, et al. investigated theassociation between zinc levels in the hair of normal infants withscalp hair quantity and the presence of a diaper rash. The studyindicated that hair loss and diaper rash in normal infants aresignificantly associated with a reduction in hair zinc concentration.(10)Another case reported progressive diffuse hairloss with hair dryness and brittleness due to a deficiency indietary zinc.

(11) However, an association between serum zinc levels andhair loss has not been well studied in the pediatric population. Therefore, theaim of this study is to assess serum zinc levels in children with hair loss andto find characteristics that predict particularly low zinc levels.Materials and methods:Patientpopulation:This wasan out-patient clinic based prospective observational study done in pediatricsand dermatology clinics in Al-Karak teaching hospital affiliated with MutahUniversity, Jordan. The ethical committee approved the study protocol.

Informedconsent from the patients’ parents was obtained prior to enrolment in thestudy. Aprotocol was developed and implemented to collect the data of all pediatricpatients who were seen at the pediatrics and dermatology clinics from January2014 to January 2017. All patients who were complaining of hair loss (partialor diffuse), change in hair texture, regression of hair growth, or who werefound to have hair loss or scalp disorders on physical examination, as well ashaving confirmed low serum zinc levels were included in this study. Patientswith normal hair, normal serum zinc levels, or were taking multivitaminsupplementations were excluded from the study. The total number of patientsscreened was 5200 (2800 in dermatology clinics and 2400 in pediatrics clinics).Historytaking and physical exam methodology:Adetailed history was taken regarding hair symptoms including; the type of hairloss (partial or diffuse), scalp symptoms, changes in hair texture and thegrowth of hair.

In addition, a history of any hair changes in other parts ofthe body including the eyebrows or eyelashes was taken. The way patientspresented themselves to their physician was classified into three groups. Group1 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 concernalongside another more significant concern to them, and group 3 was defined asthose who did not complain of hair loss.

In addition, a detailed history wastaken about hair grooming/habit tics, nail changes, other cutaneous changes,systemic diseases (e.g. cystic fibrosis, celiac disease, cow milk allergy, andenteritis), family history of similar conditions or autoimmune disease, anddrug history. Economic status was assessed by the family income per capita, andwas classified according to the World Bank new data on July 1, 2017, as high,upper-middle, lower-middle, or low income. Dietary history was also taken, and focused mainly on pickyeating behavior that excluded animal products (e.g.

meat, poultry, and fish) aswell as having a lower diversity of food. Patients that showed signs of pickyeating at around the ages of 2 to 3 years were considered to have early-onsetpicky eating, whereas patients that started at about 4.5-5.5 years wereconsidered to have late-onset picky eating.

Patients who started off in theearly-onset picky eating category and continued to have picky eating behaviorwere considered to be persistent picky eaters.(12).{ Macro- and micronutrient intakes inpicky eaters}Scalpexamination included the skin of the scalp (presence of erythema, scales, andfollicular 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.

Anthropometricmeasures assessed included weight for height, height for age, and weight forage. The values for each nutritional index were converted into Z scores(Standard deviations) using the data provided by the 2000 CDC growth charts.(13)Z scores between +1 and -1 were considered normal, between -1 and -2 low,and below -2 very low.Biochemicalmethodology:Totalzinc concentration in the patients’ serum was measured using an automatedchemistry analyzer (Biosystem BT-350 module, Spain) according to themanufacturer protocol (is the manufacturer protocolrelated to the method of measuring zinc, or related to the definition of lowzinc levels? I guessed the former), low zinc level was defined by serumzinc less than 70 µg/dL. Hemoglobin, ferritin, and vitamin D levels were alsoobtained to assess nutritional status. Anemia was defined as a hemoglobin levelless than 11 g/dL. Ferritin was considered to be deficient when below 12 ng/mLfor children less than 5 years of age and below 15 ng/mL for those above 5years. Vitamin D was considered to be deficient when below 25 nmol/L.

(14)Otherinvestigations carried out included a sweat chloride test for cystic fibrosis, aswell as a Tissue Transglutaminase antibody IgA screen for celiac disease. Thesetests were performed in some cases to further confirm the presence of systemicdiseases. Blood tests for thyroid function, antinuclear antibody, and other autoantibodies were also performed where necessary insome cases.Statisticalmethodology:In thisstudy four main statistical tests were used. Namely, the independent Student’sT-test, the ANOVA, the Pearson Chi-Square test, and the Fisher exact test. The Student’sT-test and the ANOVA were used to analyze the mean zinc levels. The Chi-Squaretest was used to find an association between two categorical variables.

The Fisherexact test was used when a Chi-Square test was not a viable option. Thetolerated 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. SPSSV. 21.0 software was used for the statistical analysis in this study.

Results:Of the5200 cases screened, 401 cases had hair loss. Of those with hair loss 162 hadzinc deficiency. Therefore, the prevalence of zinc deficiency in this pediatricpopulation with hair loss was 40.4%. Figure x demonstratesthe distribution of patients in detail.

Amongthe 162 patients analyzed in this study, 61% were female and 39% male. The ageranged from 1 month to 14 years with a mean of 4.8 ± 3.

1 years. When categorizing the patients based on how theypresented to the physician 21.6% were within group 1, 32.1% were within group2, and 46.3% were within group 3.

On physical examination 31.5% had diffusehair loss, 14.2% had patchy hair loss, 58% had a scaly scalp, 95.1% had hairtexture or color changes, and 30.2% had other skin manifestations.7.4% hadan 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, and12.3% the mother and a sibling. According to the World Bank organizationclassification 4.9% had a low household income, 59.9% had a lower-middlehousehold income, 33.3% had an upper-middle household income, and 1.9% had ahigh 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 weightto height z score.The meanzinc level was 51.3 ± 11.2 ?g/dL.

Table xsummarizes the factors associated with differences in mean zinc levels. Therewas no statistically significant difference between the mean zinc level inmales and females, or between the age groups. Although the sex of the patienthad no significant association with zinc levels when looking at the patientsample overall, when looking only at patients who complained primarily of hairloss (i.

e. Group 1), it was found that males had a significantly lower meanzinc level than females. Furthermore, females were almost 5 times more likelyto complain primarily of hair loss than males (P<0.001). Ferritindeficiency was not associated with a lower mean zinc level.

However, both anemicand vitamin D deficient patients were associated with a lower mean zinc levelthan normal patients. Interestingly, the presence or absence of either anemiaor vitamin D deficiency was not correlated with how the patient presentedthemselves to the physician with hair loss (P=0.140 for anemia, and P=0.

584 forvitamin D).Patientswho were aware of their hair loss (Groups 1 and 2) had a significantly lowermean zinc level than patients who were not (group 3). The presence of diffusehair loss, patchy hair loss, a scaly scalp, hair texture or color changes, orskin manifestations were all associated with a lower mean zinc level. Patientswith lower weight for age z scores, height for age z scores, and weight forheight z scores were associated with a lower mean zinc level. The presence of afamily history of hair loss was associated with a decreased mean zinc level.

Furthermore,there was no major difference between mean zinc levels in the four differentfamily income categories.Themajority of this study population (92.6%) did not have any systemic diseases, theirzinc deficiency and hair loss was most likely due to dietary problems. Of the 162 patients in this study, 137 have beengrouped 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 pickyeaters, 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) (Move this p-value to table? Move themean values also to table? – avoid repeating info).

Patientswho were found to have an underlying systemic illness had a statisticallysignificant lower mean zinc level than those who did not (36.6 and 52.5 ?g/dL respectively, P<0.001, T=5.

1) (Move this totable?). Of the 13cases with underlying systemic diseases, 11 cases had diseases that are known causes of zincdeficiency and presented with hair loss along with another major complaint (is thiswhat you meant?). Among them three cases had celiac disease(Mean zinc: 31.6?g/dL), three cases had cystic fibrosis (27?g/dL),four cases had cow milk allergy (31.

6 ?g/dL), a single case had congenitalhypotherodism (zinc level?) and another single casehad hereditary acrodermatitis enteropathica (zinclevel?) (3+3+4+1+1 = 12 cases, not 11 or 13?). Discussion:Zinc canbe a cofactor for almost every known subtype of human enzyme, hence itsdeficiency has a very wide range of presentations, which can cause a delay indiagnosis 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 pustulardermatitis, alopecia, diarrhea, emotional disorders, weight loss, recurrentinfections, hypogonadism in males, neurosensory disorders, and problems withthe healing of ulcers.

(15) Being able to recognize a likely case ofzinc deficiency and estimate the severity of this deficiency using mainlyclinical information can be invaluable in avoiding many more complications.Theprevalence 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 inadults, but is a problem in children as well and should be considered as partof the differential diagnosis.In thisstudy it was found that if patients were aware of their hair loss and complainabout it (either as a primary complaint or a secondary complaint), they aremore likely to have a lower zinc level than those who were only found to havehair loss on physical examination. Patchy hair loss seems to be the sign withthe lowest associated zinc level. Diffuse hair loss, hair texture and colorchanges, a scaly scalp, and skin manifestations also predict low zinc levels. Thepresence of anemia or vitamin D deficiency lowered the likely mean zinc levelto be found. This could mean that the presence of anemia and vitamin Ddeficiency are hints towards a nutritional defect that also happens to causezinc deficiency.

Interestingly, although iron nutritional sources overlapsignificantly with zinc sources,(16, 17) low ferritin did not have astatistically significant correlation with lower zinc levels. This was probablydue 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 anincreased likelihood to present with hair loss as a primary complaint.Both sexand age were poor predictors of zinc levels when looking at the whole patientsample. However, it seems that when males complain of hair loss primarily theyhave a much more severe zinc deficiency than their female counterparts who havethe same complaint. Females were almost 5 times more likely to complain of hairloss as their primary complaint than males. One possible explanation could bethat parents have a higher cosmetic concern for females, and so males presentlater with a more severe deficiency as well as other non-hair related symptoms.

Height-for-age is an important functional indicatorthat has been found in previous studies to help establish the nutritionalstatus of zinc deficiency.(18) In this study, a low or very lowweight for age z score, height for age z score, weight for height z score, allpredicted lower serum zinc levels than people with normal z scores. Thepresence of a family history or an underlying illness also predicted lowerserum zinc levels.

The family income of the patient did not predict serum zinclevels.  Dietary inadequacies may arise from low dietary zinc intake orpoor absorption of dietary zinc.(19)In low-income countries diets are predominantly plant-based foods,especially cereals that are known to have a high phytate content, whichinhibits the absorption of zinc. Young children have been shown to have a greatrisk of zinc deficiency, which is likely due to their increased dietary zincrequirements needed to sustain their growth.(20) Because there is no functional reserve or body store of zinc,except possibly in infants(21), a relativelycontinuous adequate dietary supply is required. Most of the patients in this study (92.6%) hadhair loss due to zinc deficiency associated with dietary problemsrather than underlying diseases.

The serum zinc deficiency and hair loss inpatients with dietary problems were less severe and progressed slower incomparison to patients with underlying diseases. This provides the conclusionthat mild to moderate zinc deficiency is common in low-resource settings.  Pickyeaters were associated with reduced consumption of whole-grain products, fish,seafood, meat, and unsweetened cereals and an increased consumption of savorysnacks, confectionary cereals and French fries compared to non-picky eaters.(22,23)Based on this fact, we can argue that such low diversity of food in pickyeaters can increase the risk of zinc deficiency which may be attributed totheir hair loss.

In this study persistent picky eaters had the lowest zinclevel among all type of picky eaters. Moreover, the picky eating behavior waslikely associated with how a patient presents (?2 = 21.71, P=0.001), patientswho were never picky eaters were less likely to complain of hair loss, incomparison to patients who had some sort of picky eating. Persistent pickyeating especially was the most likely to have hair loss complaints onpresentation.

 Acrodermatitisenteropathica is one of the severest forms of human zinc deficiency, althoughthe total body zinc is not greatly reduced, the serum zinc concentrations aretypically extremely low (e.g. <30 ?g/dL.(24) This is an exampleof a genetic hair disorder caused by nutritional zinc deficiency(25).Other examples of poor absorption of dietaryzinc are celiac disease and cystic fibrosis.

 The presentation of infants and young children with celiac disease overlapswith several of the features of zinc deficiency: anorexia, diarrhea, and short stature.(25,26) Zinc deficiency has been documented in young infants identified bynewborn screening prior to initiation of pancreatic enzyme therapy.(26, 27) In settings without newbornscreening, presentation is typically later in infancy, with associated growthfaltering, diarrhea, and dermatitis similar to Acrodermatitis enteropathica.

(27,28) The zincdeficiency in these two diseases may be attributed to patients hair loss(not sure what this means, I think you mean theopposite hair loss attributed to zinc deficiency. And the two diseases arecystic fibrosis and celiac?). The new finding in this study regardingsystemic diseases was the presentation of hair loss in patients with cow milk allergy;it may be argued that zinc deficiency due to chronic enteritis may augment hair loss beside their skin manifestation (May cause/increase hair loss as well as other skinmanifestations?).  Inthis study, systemic diseases were not a verycommon cause of zinc deficiency associated hair loss. However, their symptoms were more obvious, particularly alopecia,and their zinc deficiency was more severe.  Interestingly,the most severely affected patient was a two month old underweight baby with acrodermatitisenteropathica complicated with severe failure to thriveand hair loss that included almost the whole scalp with a serum zinc level of25 ?g/dL.The patient had a positive clinical progression after zinc supplementation; theskin lesions and alopecia disappeared when the serum zinc levelwas raised above 60 ?g/dL.

 Hypothyroidismis a well-known cause of hair loss. However, zinc and other trace elements arerequired for the synthesis of thyroid hormones, and so zinc deficiency canresult in hypothyroidism, which can be masked in children. Furthermore, hypothyroidismcan result in further zinc deficiency as thyroid hormones are essential for theabsorption of zinc. Zinc supplements have been shown to improve hair lossattributed to hypothyroidism. (29) Mentionthe hypothyroidism case(s) here?It hasbeen reported that severe zinc deficiency associated with a severe type of hairloss was treated with zinc supplementation for 6 months as well as improvingthe patient’s diet.(11) In this study similar findings were alsofound. All patients with zinc deficiency were started on zinc supplementationin a dose of (0.5-1mg) per day for 3-6 months, in addition to modifying theirdiets.

The hair loss stopped in 6-8weeks, and follow up in after a few months showed no evidence of alopecia withnormal looking hair, except in the patient caused by hereditary acrodermatitisenteropathica and the patients with cystic fibrosis who were severely affectedand needed higher dose and longer duration of treatment.Interestingly, thereis some evidence to support that blind treatment with zinc supplements for hairloss without documenting the actual low serum zinc level may exacerbate thehair loss and are not recommended in the absence of a proven deficiency.(30)Insummary, there are many predictive factors for the severity of zinc deficiencyin pediatric patients with hair related symptoms or signs. Patchy hair loss,very low body weight for age, persistent picky eating and the presence of anunderlying illness such as celiac disease and cystic fibrosis seem to be thefour characteristics associated with the lowest mean zinc levels. Furtherstudies to examine the usefulness of the clinical assessment of hair loss andskin manifestations to directly predict zinc deficiency related complicationssuch as recurrent infections would be extremely useful to clinicians. 

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