Hair Analysis

Number: 0300

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses hair analysis.

1. Experimental and Investigational

   The following procedures are considered experimental and investigational because the effectiveness of these approaches has not been established (not an all-inclusive list):

   1. Chemical hair analysis, except for diagnosis of suspected chronic arsenic poisoning;
   2. Hair analysis of brain-derived neurotrophic factor (BDNF) as a predictor of developing psychopathological symptoms in childhood.

2. Policy Limitations and Exclusions 

   Note: Microscopic evaluation of hair structure (trichogram) may be medically necessary as part of the work-up of members with alopecia or abnormal-appearing or abnormally growing hair. 

   Note: Although hair samples may be used for verifying abuse of illicit substances in persons who wish to evade detection, its use in this situation is not considered treatment of disease.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Chemical hair analysis:
CPT codes covered if selection criteria are met:
82175	Arsenic
83015	Heavy metal (eg, arsenic, barium, beryllium, bismuth, antimony, mercury); qualitative, any number of analytes
HCPCS codes not covered for indications listed in the CPB:
P2031	Hair analysis (excluding arsenic)
ICD-10 codes covered if selection criteria are met:
T37.8X1A - T37.96XS	Poisoning by, adverse effect of and underdosing of other and unspecified systemic anti-infectives and antiparasitics
T57.0X1A - T57.0X4S	Toxic effect of arsenic and its compounds
Z13.88	Encounter for screening for disorder due to exposure contaminants [suspected chronic arsenic poisoning]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
D53.0	Protein deficiency anemia
E58, E59, E60, E61.0 - E61.9	Mineral deficiencies
E70.0 - E88.9	Metabolic disorders
F84.0	Autistic disorder
J30.0 - J30.9	Vasomotor and allergic rhinitis
J45.20 - J45.998	Asthma
L20.0 - L20.9	Atopic dermatitis
L27.2	Dermatitis due to ingested food
L50.0 - L50.9	Urticaria
R82.5 - R82.6, R89.2 - R89.3	Other and unspecified abnormal findings in urine
T36.0X1A - T37.5X6S, T38.0X1A - T50.996S	Poisoning by, adverse effects of and underdosing of drugs, medicaments and biological substances
T63.00XA - T63.94XS	Toxic effect of contact with venomous animals and plants
T78.00XA - T78.2XXS, T88.6XXA - T88.6XXS	Anaphylactic shock
T78.3XXA - T78.3XXS	Angioneurotic edema
T78.40XA - T78.40XS	Allergy, unspecified
Z13.21 - Z13.29	Encounter for screening for nutritional, metabolic and other endocrine disorders
Z13.39	Encounter for screening examination for other mental health and behavioral disorders [prediction of developing psychopathological symptoms in childhood]
Z91.010 - Z91.09	Allergy status, other than to drugs and biological substances
Microscopic evaluation of hair structure (trichogram):
CPT codes covered if selection criteria are met:
96902	Microscopic examination of hairs plucked or clipped by the examiner (excluding hair collected by the patient) to determine telogen and anagen counts, or structural hair shaft abnormality
ICD-10 codes covered if selection criteria are met:
L65.0 - L65.9	Other nonscarring hair loss [abnormal alopecia]
L67.0, L67.8 - L67.9	Hair color and hair shaft abnormalities
L73.1, L73.8 - L73.9	Other follicular disorders

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Background

Hair analysis has been proposed as an aid in the diagnosis of disorders such as mineral or protein deficiency or mineral toxicity.  Hair analysis has not been proven to be effective in ascertaining mineral or metabolic imbalances or IgE-mediated allergic diseases.  Hair analysis has also not been proven to be of use in either the diagnosis or treatment of autism.

Because arsenic is taken up and bound in hair and fingernails, analysis of hair and nails have been used to detect chronic arsenic exposure (Goldman, 2008).  However, in a setting in which air exposure is a consideration, as in an industrial environment, it is very difficult to remove exogenous arsenic from hair, and therefore to get a reliable reading.  Also a lack of standardization of analysis contributes to the variability of results from hair and nail testing.  Goldman (2008) explained that commercial laboratory hair analyses for multiple elements including arsenic are highly inaccurate.  Determination of arsenic in hair and nails has been most useful in epidemiological studies performed to evaluate environmental exposures of populations to inorganic arsenic; it is less useful in the evaluation of an individual patient (Goldman, 2008).

Microscopic evaluation of hair structure (trichogram) may be indicated as part of the work-up of members with alopecia or abnormal-appearing or abnormally growing hair.  Hair may be examined under the microscope to determine the number of hairs that are actively growing (anagen phase) versus the resting phase (telogen).  In addition, microscopic examination of clipped hair can reveal structural abnormalities of the hair bulb or shaft.

Rahman et al (2009) determined the concentration of trace elements present in scalp hair sample of schizophrenic patients and examined the relationship between trace elements level and nutritional status or socioeconomic factors.  The study was conducted among 30 schizophrenic male patients and 30 healthy male volunteers.  Hair trace element concentrations were determined by flame atomic absorption spectroscopy and analyzed by independent t-test, Pearson's correlation analysis, regression analysis, and analysis of variance (ANOVA).  Mn, Zn, Ca, Cu, and Cd concentrations of schizophrenic patients were 3.8 +/- 2.31 microg/gm, 171.6 +/- 59.04 microg/gm, 396.23 +/- 157.83 microg/gm, 15.40 +/- 5.68 microg/gm, and 1.14 +/- 0.89 microg/gm of hair sample, while those of control subjects were 4.4 +/- 2.32 microg/gm, 199.16 +/- 27.85 microg/gm, 620.9 +/- 181.55 microg/gm, 12.23 +/- 4.56 microg/gm, and 0.47 +/- 0.32 microg/gm of hair sample, respectively.  The hair concentration of Zn and Ca decreased significantly (p = 0.024; p = 0.000, respectively) and the concentration of Cu and Cd increased significantly (p = 0.021; p = 0.000, respectively) in schizophrenic patients while the concentration of Mn (p = 0.321) remain unchanged.  Socioeconomic data reveals that most of the patients were poor, middle-aged and divorced.  Mean body mass indices (BMIs) of the control group (22.26 +/- 1.91 kg/m(2)) and the patient group (20.42 +/- 3.16 kg/m(2)) were within the normal range (18.5 to 25.0 kg/m(2)).  Pearson's correlation analysis suggested that only Ca concentration of patients had a significant positive correlation with the BMI (r = 0.597; p = 0.000) which was further justified from the regression analysis (R (2) = 44 %; t = 3.59; p = 0.002) and 1-way ANOVA test (F = 3.62; p = 0.015).  A significant decrease in the hair concentration of Zn and Ca as well as a significant increase in the hair concentration of Cu and Cd in schizophrenic patients than that of its control group was observed, which may provide prognostic tool for the diagnosis and treatment of this disease.  However, further work with larger population is suggested to examine the exact correlation between trace element level and the degree of disorder.

Guidelines from the National Institute for Health and Clinical Excellence (2011) recommended against the use of hair analysis in the diagnosis of food allergy.  An NIAID expert panel (Boyce et al, 2010) made similar recommendations against the use of hair analysis in food allergy.  Guidelines from the American Academy of Asthma, Allergy and Immunology (Wallace et al, 2008) state that hair analysis has no diagnostic validity in rhinitis. Autism guidelines from the Singapore Ministry of Health (2010) recommend against the use of hair mineral analysis for autism.

Albar et al (2013) stated that recently, hair cortisol has become a topic of global interest as a biomarker of chronic stress.  Different research groups have been using different methods for extraction and analysis, making it difficult to compare results across studies.  A critical examination of the reported analytical methods is important to facilitate standardization and allow for a uniform interpretation.  These researchers qualitatively compared 4 published procedures from laboratories in Germany, the Netherlands, the United States of America and Canada.  Multiple aspects of their procedures were compared.  A major difference among the laboratories was the enzyme-linked immunosorbent assay (ELISA) kit used: the Canadian laboratory used the kit from ALPCO Diagnostics (Salem, MA), the American laboratory used the kit from DRG International (Springfield, NJ), the German laboratory used the kit from DRG Instruments GmbH (Marburg, Germany), or IBL (Hamburg, Germany), and the Dutch used the kit from Salimetrics (Suffolk, UK).  In addition, there were noted differences in hair mass used as well as washing and extraction procedures.  The range of hair cortisol levels determined in healthy volunteers by the 4 groups was within 2.3-fold: Koren, 46.1 pg/mg; Van Rossum, 29.72 pg/mg; Kirschbaum, 20 pg/mg and Laudenslager ~ 27 pg/mg.  The authors concluded that the relative similarities in hair cortisol values in volunteers among the 4 laboratories should facilitate a quality assurance exchange program, as a necessary step toward clinical use of this novel test.

Karlen and colleagues (2013) examined cortisol concentrations in hair as biomarker of prolonged stress in young children (n = 100) and their mothers and the relation to perinatal and socio-demographic factors.  Prolonged stress levels were assessed through cortisol in hair.  A questionnaire covered perinatal and socio-demographic factors during the child's first year of life.  Maternal hair cortisol during the second and third trimester and child hair cortisol at year 1 and 3 correlated.  Child cortisol in hair levels decreased over time and correlated to each succeeding age, between years 1 and 3 (r = 0.30, p = 0.002), 3 and 5 (r = 0.39, p < 0.001), and 5 and 8 (r = 0.44, p < 0.001).  Repeated measures gave a significant linear association over time (p < 0.001).  There was an association between high levels of hair cortisol and birth weight (β = 0.224, p = 0.020), non-appropriate size for gestational age (β = 0.231, p = 0.017), and living in an apartment compared with a house (β = 0.200, p = 0.049).  In addition, these investigators found high levels of cortisol in hair related to other factors associated with psychosocial stress exposure.  The authors concluded that correlation between hair cortisol levels in mothers and their children suggested a heritable trait or maternal calibration of the child's hypothalamic-pituitary-adrenocortical axis.  Cortisol output gradually stabilizes and seems to have a stable trait.  They stated that cortisol concentration in hair has the potential to become a biomarker of prolonged stress, especially applicable as a non-invasive method when studying how stress influences children's health.

Russell et al (2014) noted that cortisol is assumed to incorporate into hair via serum, sebum, and sweat sources; however, the extent to which sweat contributes to hair cortisol content is unknown.  In this study, sweat and saliva samples were collected from 17 subjects after a period of intensive exercise and analyzed by salivary ELISA. Subsequently, an in-vitro test on exposure of hair to hydrocortisone was conducted. Residual hair samples were immersed in a 50-ng/ml hydrocortisone solution for periods lasting 15 mins to 24 hrs, followed by a wash or no-wash condition.  Hair cortisol content was determined using the authors’ modified protocol for a salivary ELISA.  Post-exercise control sweat cortisol concentrations ranged from 8.16 to 141.7 ng/ml and correlated significantly with the log-transformed time of day.  Sweat cortisol levels significantly correlated with salivary cortisol concentrations.  In-vitro hair exposure to a 50-ng/ml hydrocortisone solution (mimicking sweat) for 60 mins or more resulted in significantly increased hair cortisol concentrations.  Washing with isopropanol did not affect immersion-increased hair cortisol concentrations.  The authors concluded that human sweat contains cortisol in concentrations comparable with salivary cortisol levels.  The findings of this study suggested that perfuse sweating after intense exercise may increase cortisol concentrations detected in hair.  This increase likely cannot be effectively decreased with conventional washing procedures and should be considered carefully in studies using hair cortisol as a biomarker of chronic stress.

Boscolo-Berto et al (2014) evaluated the diagnostic performance of ethyl glucuronide in the 3-cm proximal scalp hair fraction (HEtG) as a marker of chronic excessive drinking.  In July 2012/May 2013, after a systematic search through the MEDLINE, OVID/EMBASE, WEB OF SCIENCE, and SCOPUS databases, 8 studies were included in the pooled analysis that reported raw single data on HEtG concentration and self-reported daily alcohol intake (SDAI).  A receiver operating characteristic curve analysis and a Spearman rank-order correlation test were used.  A meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane recommendations, comprising quality and bias assessments.  The pooled analysis showed that 30 pg/mg could be a useful cut-off value for HEtG to detect an SDAI greater than 60 g/d and demonstrated a parabolic direct correlation between HEtG and SDAI data [rho 0.79; 95 % confidence interval (CI): 0.69 to 0.87; p < 0.001].  The meta-analysis found an overall HEtG sensitivity of 0.96 (95 % CI: 0.72 to 1.00) and a specificity of 0.99 (95 % CI: 0.92 to 1.00); a nomogram to predict the post-test probability of exhibiting the targeted condition in the general population was built.  Significant variability among the included studies was detected, which was mainly explained by true heterogeneity in the presence of publication bias.  The authors concluded that HEtG is a promising marker for identifying chronic excessive drinking.  Nonetheless, they stated that larger and well-designed population studies are needed to draw any definitive conclusions on the significance and appropriateness of its application in the forensic setting.

Mao et al (2014) stated that trace elements play an important role in maintaining the normal metabolic and immune function.  The onset of recurrent respiratory tract infection (RRI) is associated with the immune function, genetic factors and nutritional status.  However, the association between the levels of trace elements and RRI remains inconclusive.  These researchers investigated the alterations of hair levels of zinc (Zn), copper (Cu) and iron (Fe) in Chinese children with RRI by performing a meta-analysis.  A pre-defined electronic databases search was performed to identify eligible studies for the analysis of hair Zn, Cu or Fe levels in Chinese children with RRI.  A total of 13 studies were included; RRI patients displayed significantly lower levels of hair Zn (13 studies, random effects standard mean difference (SMD): - 1.215, 95 % CI: - 1.704 to - 0.725, p < 0.0001), Cu (11 studies, random effects SMD: - 0.384, 95 % CI: - 0.717 to - 0.052, p = 0.023) and Fe (12 studies, random effects SMD: - 0.569, 95 % CI: - 0.827 to - 0.312, p < 0.0001) compared with controls.  No evidence of publication bias was observed.  Sensitivity analysis did not change the results significantly.  The authors concluded that deficiency of Zn, Cu and Fe may be contributing factors for the susceptibility of RRI in Chinese children.  However, more studies in different ethnicities should be performed in the future.

Wei et al (2015) compared the hair cortisol levels between patients with depression and healthy controls.  Hair cortisol levels of 22 first-episodic and 13 recurrent female patients with depression and 30 healthy controls were measured and compared using the electrochemiluminescence immunoassay.  The relationship between hair cortisol levels and Hamilton depression scale (HAMD) or Hamilton anxiety scale (HAMA) scores were also examined.  Before disease episode, no significant differences were observed among healthy controls, first-episodic patients and recurrent patients.  In disease episode, the hair cortisol level in first-episodic patients was significantly higher than that in healthy controls or recurrent patients, while no significant difference was observed between recurrent patients and healthy controls.  No significant correlation was found between HAMD or HAMA scores and hair cortisol levels in patients.  The authors concluded that these findings indicated that hair cortisol levels increased in disease episode in first-episodic, but not recurrent patients with depression, which may suggest that episodes of disease have influence on cortisol levels.  The main drawbacks of this study were:

1. long-term effects of anti-depressants on the results cannot be excluded without detailed medication information of the recurrent patients, and
2. sample sizes were relatively small.

Liu et al (2015) examined the association between Zn levels and myocardial infarction (MI) using a meta-analysis approach.  These investigators searched articles in the PubMed, OVID, and ScienceDirect published as of November 2014.  A total of 13 eligible articles with 2,886 subjects from 41 case-control studies were identified.  Overall, pooled analysis indicated that subjects with MI had lower Zn levels than healthy controls (standardized mean difference (SMD) = -1.848, 95 % CI: -2.365 to -1.331).  Further subgroup analysis found that subjects with MI had lower Zn levels than healthy controls in serum (SMD = -1.764, 95 % CI: -2.417 to 1.112) and hair (SMD = -3.326, 95 % CI: -4.616 to -2.036), but not in toenail (SMD = -0.396, 95 % CI: -1.114 to 0.322).  The subgroup analysis stratified by type of Zn measurement found a similar pattern in inductively coupled plasma-atomic absorption spectrometry (ICP-AAS) (SMD = -2.442, 95 % CI: -3.092 to -1.753), but not in neutron activation analysis (NAA) (SMD = -0.449, 95 % CI: -1.127 to 0.230]).  Lower Zn levels in MI patients were found both in male (SMD = -3.350, 95 % CI: -4.531 to -2.169]) and female (SMD = -2.681, 95 % CI: -3.440 to -1.922]).  And the difference of Zn levels according to MI in Asia (SMD = -2.555, 95 % CI: -3.267 to -1.844) was greater to that among the population in Europe (SMD = -0.745, 95 % CI: -1.386 to -0.104), but no difference was found in Oceania (SMD = -0.255, 95 % CI: -0.600 to 0.089]).  The authors concluded that this meta-analysis indicated that there is a significant association between Zn deficiency and MI.  They suggested that a community-based, long-term observation in a cohort design should be performed to obtain better understanding of causal relationships between Zn and MI, through measuring hair Zn at baseline to investigate whether the highest Zn category versus lowest was associated with MI risk.

Zhang et al (2016) noted that cadmium is a heavy metal that has been suggested to be a carcinogen by evidence.  A number of published studies have investigated the association between cadmium levels and prostate cancer, but the results were inconsistent.  These researchers performed a meta-analysis to get a precise estimate of this subject.  After a careful searching and screening, a total of 11 publications containing 14 separated studies were included.  Based on a random-effect model, the pooled data showed that cadmium levels of prostate tissues (SMD = 3.17, 95 % CI: 0.60 to 5.74, p < 0.05) and plasma (SMD = 4.07, 95 % CI: 2.01 to 6.13, p < 0.05) were significantly higher in prostate cancer patients than those in the healthy controls.  No difference of hair and nail cadmium levels between the prostate cancer cases and the controls was found.  The authors concluded that these data suggested that cadmium exposure might exert an influence on the tumorigenesis of prostate tissues; future investigations with large sample sizes are needed to verify the results.

Evaluation of Attention Deficit Hyperactivity Disorder

In a case-control study, Tabatadze and colleagues (2018) evaluated hair micro-elemental status in children with attention deficit hyperactivity disorder (ADHD), determined micro-elemental misbalances and heavy metal concentrations and examined its impact on child behavior.  These investigators studied 70 children, mean age of 6 to 8 year.  Target group involved 35 children with ADHD; control group included 35 children of same age with normal behavior.  Groups were homogenous based on different characteristics.  To diagnose behavioral problems multi-profile group (pediatrician, neurologist, psychologist) assessment was used and final diagnostic was based on DSM V and ICD-10 criteria.  Micro-elemental status was detected in the hair, with roentgen-fluorescence spectrometer method.  These researchers studied the content of 27 micro-elements (Zn, Fe, Cu, Mn, Co, Se, K, Cr, S , Cl, ,Ag ,V, Ni, Rb, Sr, Mo, Sr,, Pb, Hg, Br, Ti, Ba, As, Zr, Sb, Sn, Cd) in the hair in target and control groups.  Computer program SPSS - 21 was used for statistical analysis.  The results of this study revealed deficiency of major elements (Fe, Mn, Co, Se) in target group; and deficiency of Zn and Cu in both (control and target) groups, but the mean concentrations of Mn (sig 0,200; p > 0,05), Cu (sig 0,813; p > 0,05) and Se (sig 0,320; p > 0,05) did not show significant difference between control and target groups.  Only in case of Zn (sig 0,000; p < 0,05), Fe (sig0,000; p < 0,05) and Co (sig 0,000; p < 0,05) deficiency that significant values and meaningful associations between micro-element's deficiency and ADHD were observed.  This study did not reveal any changes in other 17 elements (K, Cr, S, Cl, Ag, V, Ni, Rb, Sr, Mo, Sr, Ba, As, Zr, Sb, Sn, Cd) levels.  These investigators detected contamination with Pb, Hg, and Ti in both groups , but there were significant difference in Pb (sig 0,000; p < 0,05) and Hg (sig 0,000; p < 0,05) values between control and study groups, while difference of Ti (sig 0,177; p > 0,05) level was not significant.  The authors concluded that the findings of this study suggested that Zn, Fe and Co deficiency as well as contamination with high Pb and Hg were associated with ADHD.  These preliminary findings need to be further investigated.

Evaluation of Schizophrenia and Bipolar Disorders Associated with Childhood Maltreatment

Aas and colleagues (2019) stated that the neural diathesis-stress model is useful to understand schizophrenia (SZ) and bipolar (BD) disorders.  Childhood maltreatment could affect the hypothalamic-pituitary-adrenal (HPA)-axis and lead to chronic changes in stress-sensitivity, which can be measured with hair cortisol concentrations (HCC), representing long-term, cumulative cortisol levels.  These investigators examined if childhood trauma experiences were associated with chronic changes in the HPA axis in severe mental disorders.  Participants with SZ or BD (n = 63) and healthy controls (n = 94) were included, and HCC was measured by ELISA.  History of childhood maltreatment was assessed using the Childhood Trauma Questionnaire (CTQ).  Global function and symptom levels were obtained using the Global Assessment of Functioning (GAF) Scale and the Positive and Negative Syndrome Scale (PANSS).  A neuropsychological test battery (MATRICS) was performed to assess cognitive functions.  This study demonstrated for the first time that patients with a history of childhood maltreatment had higher HCC relative to both healthy controls and patients without a history of childhood maltreatment (p = 0.01, ƞp2 = 0.046).  In addition, patients experiencing a mood episode had higher HCC than patients in remission (p = 0.03).  Lastly, these researchers were the first to show that patients with higher HCC had poorer cognitive performance, specifically working memory (p = 0.01).  All associations were irrespective of diagnostic group.  A factor analysis confirmed a subgroup within the patients characterized by childhood maltreatment and elevated HCC.  The authors concluded that these findings supported the neural diathesis-stress model in SZ and BD pointing to long-term changes in HPA-axis following childhood maltreatment experiences.  The clinical significance of this association needs to be further investigated.

Assessment of Hair Nickel and Chromium Levels in Patients with a Fixed Orthodontic Appliance

Imani and colleagues (2019) noted that nickel (Ni) and chromium (Cr) can cause immunological sensitivity and adverse biological and cytotoxic effects. These researchers examined hair levels of these metals in patients undergoing fixed orthodontic treatment compared with controls.  A total of 5 databases – PubMed, Web of Science, Scopus, Cochrane Library, and ScienceDirect – were searched up to January 2018 for evaluation of the hair levels of Ni and/or Cr in patients undergoing fixed orthodontic treatment.  To evaluate the study quality, the Newcastle-Ottawa Scale was used (NOS), and to compare hair Ni and Cr levels in the cases compared with the controls, a random-effects meta-analysis was performed by Review Manager 5.3 using SMDs and 95 % CIs.  Out of 38 studies in the databases searched, 6 studies were included in the meta-analysis.  The pooled SMD of hair Ni levels between the cases and controls was 0.95 μg/g (95 % CI: -0.09 to 1.99; p = 0.07), which showed that the Ni level was similar in the cases compared with the controls, and that for hair Cr levels was 0.88 μg/g (95 % CI: -0.45 to 2.21; p = 0.20), so the Cr level was similar in the cases compared with the controls.  The authors concluded that due to the slightly elevated hair levels of Ni and Cr in the subjects undergoing fixed orthodontic therapy, changing the components of fixed orthodontic appliances can be considered as an acceptable solution in the future.  These investigators stated that future studies need to examine the levels of these ions in serum and saliva of patients for more accurate confirmation of cytotoxic and allergic effects after fixed orthodontic therapy.

The authors stated that this meta-analysis had several drawbacks.  First, duration of treatment and measurement methods were different in the studies.  Second, age and sex were not matched between the groups.  Third, there was a low number of subjects in most studies.

Inorganic Arsenic and Lead and Autism Spectrum Disorder in Children

Wang and colleagues (2019) stated that inorganic arsenic (iAs) and lead (Pb) rank first and second on the U.S. Environmental Protection Agency (EPA)'s priority list of hazardous substances.  Both are known neurotoxic metals that cause detrimental effects on brain development and result in deficits in cognitive function and behavioral performance in children.  Studies have indicated a potential link between iAs and Pb exposure and a higher risk for autism spectrum disorder (ASD).  To provide further insight into whether developmental exposure to iAs or Pb is associated with ASD, these investigators conducted a systematic review and combined data into a meta-analysis to evaluate the available human evidence on the relationships.  They systematically reviewed relevant studies published through December 30, 2018 and identified 14 studies on iAs and 37 studies on Pb exposure and their respective associations with ASD.  Among them, 8 (53.3 %) and 19 (51.3 %) studies reported a positive association for iAs and Pb, respectively, and none reported a sole inverse association.  In the following meta-analysis, these researchers found statistically significant higher iAs concentrations, in hair and in blood, for children diagnosed with ASD compared with controls across studies.  However, the findings on Pb exposure were inconsistent, with a significant association for hair Pb, no association for urinary Pb, and an inverse association for blood Pb.  After considering strengths and limitations of the body of research, the authors concluded that there is consistent evidence supporting a positive association between early life iAs exposure and diagnosis of ASD and inconsistent evidence for Pb exposure and ASD risk. They believed it is in the best interest of policy makers and the public to reduce exposures to iAs and Pb among pregnant women and children.  Furthermore, this research supports the need for large perspective human studies with accurate measurement and determination of the long-term body burden of iAs and Pb exposures to examine the impact of iAs and Pb exposures on ASD risk.

Guo and associates (2019) noted that a number of studies measured Pb levels in hair from children with ASD to detect the relationship between cumulated Pb exposure and the development of ASD, but results were inconsistent.  In a systematic review and meta-analysis of published studies, these researchers examined the actual association of hair Pb levels with ASD in children.  They searched PubMed, Embase, PsycINFO, and Cochrane Library databases (up to December 11, 2018).  The random-effects model was applied to summarize effect sizes.  Sub-group and meta-regression analyses were performed simultaneously.  A total of 20 eligible studies involving 1,787 subjects (941 autistic children and 846 healthy subjects) were included.  The results of primary analysis showed that there were no statistically significant differences in the levels of hair Pb between children with ASD and healthy individuals (Hedges's g = 0.251; 95 % CI: -0.121 to 0.623; p = 0.187).  These investigators identified 2 sources of between-study heterogeneity: analytical technology and the sample size of patients.  Additionally, no publication bias was observed in this meta-analysis.  The authors concluded that the findings of this study did not support the association of hair Pb levels with ASD in children, and the involvement of cumulated Pb exposure in the occurrence of ASD.

Evaluation of Maternal Prenatal Stress

Kim and colleagues (2020) noted that recently, biological markers of maternal prenatal stress, hair cortisol, along with saliva, blood, and urine cortisol, have received attention.  However, it is necessary to validate measuring HCC as a biomarker of perceived stress among healthy and high-risk pregnant women.  These researchers aimed to confirm the correlation between HCC and the perceived stress of pregnant women over 18 years of age.  In this systematic review, these investigators employed various search engines to extract relevant articles using specific keywords related to pregnancy, hair cortisol, and psychological stress; 4 out of 3,639 studies met the inclusion criteria.  These researchers performed a quality assessment with the help of 3 independent reviewers using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.  The correlation between HCC and perceived stress was confirmed in 1 study.  There was only 1 study on hair washing, shampoo, conditioner, and hair structure that could affect hair samples.  In 4 studies, hair samples differed in length, methods of storage, and laboratory analysis.  The review was limited to confirming the relationship between HCC and perceived stress in pregnant women based on the current evidence.  The authors concluded that studies on hair cortisol need regulated and standardized methods for collection, storage, and analysis of hair samples.  Moreover, these researchers stated that in further studies information on participants’ age, fetal gestational age, and obstetric history is needed.  In other words, it is recommended that standardized guidelines for HCC measurements should be established.  Although HCC is a non-invasive and useful measurement compared to saliva, blood, or urine cortisol, the generalizability of its validity will be established by identifying the sensitivity and specificity of HCC that reflects perceived stress.

Evaluation of Mental Disorders (Including Depression)

Psarraki and colleagues (2021) stated that literature supports a causal role of stress in major depressive disorder (MDD); and HCC has been widely used as a measure of long-term stress.  Although elevated HCC has been observed in healthy individuals experiencing chronic stress, findings regarding individuals with mental disorders have been complicated.  These investigators presented all the published research on major depression and HCC.  An extensive search of databases was carried out to identify studies that examined this question.  The initial search retrieved 142 studies, of which, 16 original articles were included in this review.  Results were contradictory; most of the studies showed no significant HCC differences between MDD patients and controls, while others indicated either higher or lower HCC in MDD patients than controls.  Higher HCC was reported in 1st depressive episode compared to recurrent MDD and controls; patients with co-morbid MDD and anxiety disorder had higher HCC than controls.  No significant HCC difference was found between patients with melancholic or atypical depression and controls.  Findings concerning HCC in post-partum depression were inconsistent.  A meta-analysis of the data extracted from 7 studies of the sample was carried out to quantify the degree of cortisol change in MDD patients versus controls.  A random effects model revealed no significant hair cortisol concentrations difference between depressed patients and healthy controls (SMD: -0.02,  95 % CI: -0.36 to 0.32).  Significant heterogeneity was identified across included studies (p = 0.002, I2 = 71 %).  The authors concluded that the disagreement among studies' results indicated that there is room for improvement in this research field.  Confounding factors independent of depression should be taken into consideration.

Malisiova and associates (2021) noted that research on hypothalamic pituitary adrenal (HPA) axis dysregulation has been associated with vulnerability to, or perseverance of, several mental disorders; however, measurements of cortisol levels in blood, saliva and/or urine have yielded variable results.  Nevertheless, cortisol analysis in scalp hair appeared to be a consistent tool for measurement of long-term exposure to stress.  These researchers carried out a systematic review of studies examining hair cortisol concentrations in patients with mental disorders in comparison with healthy controls.  This review was conducted according to PRISMA guidelines.  The electronic databases of PubMed/Medline, Web of Science and Scopus were searched for relevant articles, using a specific syntax.  A total of 582 articles were identified, of which 22 were finally included.  Patients with depression show a general trend for higher HCC than controls, whereas patients with post-traumatic stress disorder (PTSD) tend to have lower HCC.  Very little is known regarding other mental disorders, including suicidality and drug abuse.  The divergence of samples included and the timing of cortisol sampling, appeared to play an important role in the discrepancies of the findings.  Correlations of HCC with self-reported measures of stress were found, at best, inconclusive.  The authors concluded that further research should describe specific cortisol profiles for each psychiatric disorder and HCC could contribute in evaluating therapy outcomes and predicting relapses.  Obtaining information on HCC in different stages of psychiatric disorders in association with pertinent clinical variables, might help in forging a neuroendocrine model for clinical staging of mental disorders.

Hair Analysis of Brain-Derived Neurotrophic Factor (BDNF) as a Predictor of Developing Psychopathological Symptoms in Childhood

Pauli-Pott et al (2023) noted that dysregulation in the expression of neurotrophins is implicated in the pathophysiology of several mental disorders.  Peripheral brain-derived neurotrophic factor (BDNF) can be measured in hair and might represent a marker of adequate neuroplasticity regulation.  In early developmental periods, neuroplasticity regulation might be especially important; however, BDNF markers have not yet been analyzed in this regard.  In a longitudinal study, these researchers employed the hair-BDNF concentration (HBC) to examine the prediction of emerging symptoms of anxiety/depressive and attention-deficit hyperactivity disorder (ADHD) in the developmentally crucial period from pre-school to school age.  A total of 117 children (58 girls, 59 boys) participated in this trial at the ages of 4 to 5 (T1) and 8 (T2) years.  At T1, HBC was measured in a 3-cm hair segment.  At T1 and T2, symptom domains were assessed using a multi-method (clinical interview, questionnaire) and multi-informant approach.  T1 HBC was significantly negatively associated with T1 anxiety/depressive symptoms (r = -0.27) and predicted T2 anxiety disorder symptoms (r = -0.34) after controlling for the T1 symptoms.  T1 HBC also predicted T2 depressive disorder symptoms (r = -0.18) but was not associated with ADHD symptom development.  The authors concluded that prediction of anxiety/depressive symptom development by HBC was shown.  As this study was the 1st to use HBC in this context, cross-validation is needed and worthwhile.  These researchers stated that HBC might prove to constitute a useful, non-invasive early marker of risk for anxiety/depressive disorders in childhood.  The main drawback of this study was that BDNF hair analysis is a new method with a not yet large number of studies on methodological issues.

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References