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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 3  |  Page : 727-733

The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders


1 Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Medical Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Pediatrics, Quesna Central Hospital, Menoufia, Egypt

Date of Submission24-Apr-2016
Date of Acceptance26-Jun-2017
Date of Web Publication15-Nov-2017

Correspondence Address:
Mahmoud S Abou El-Khair
Department of Pediatrics, Quesna Central Hospital, Menoufia, 32631
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.218255

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  Abstract 

Objective
The aim of this study was to assess the plasma zinc (Zn)/serum copper (Cu) ratio as a biomarker in children with autism spectrum.
Background
Autism is a complex, behaviorally defined neurodevelopmental disorder characterized by significant impairments in social interaction, verbal and nonverbal communication, and restrictive, repetitive, and stereotypic patterns of behavior. The possible etiologies that precipitate autism symptoms remain controversial in many cases, but both genetic and environmental factors have been implicated. Children with autism spectrum disorder (ASD) appear to be at risk for Zn deficiency, Cu toxicity, and often have low Zn/Cu ratio.
Patients and methods
The present study was designed to be of a case–control type. It enrolled 40 children. Twenty patients with autism diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision and the Childhood Autism Rating Scales were included. The control group enrolled 20 apparently healthy children, matched to the patients' age and sex. All of them were subjected to biochemical analysis for assessment of plasma Zn level and serum Cu, followed by calculation of plasma Zn/serum Cu ratio.
Results
Plasma Zn was decreased in patients than in controls. Serum Cu was higher in patients than in controls. Lower Zn/Cu ratio was observed in cases in comparison with controls. intelligence quotient was lower in patients than in controls. There was a correlation between age and Zn/Cu ratio, but there was no correlation between Zn/Cu ratio and BMI. There was a negative correlation between Childhood Autism Rating Scales and Zn/Cu ratio. Zn/Cu correlated negatively with some selected symptom severity in autistic children and Zn/Cu ratio. According to receiver operating characteristic curve, the optimal cutoff value of serum levels of Zn/Cu was projected to be 0.81, with a sensitivity of 85% and a specificity of 85%, and the area under the curve was 0.93.
Conclusion
Our results suggested an association between blood levels of Zn and Cu with ASD among our patients, and the Zn/Cu ratio could be considered a biomarker of ASD.

Keywords: autism spectrum disorder, copper, trace elements, zinc, zinc/copper ratio


How to cite this article:
El-Meshad GM, Abd El-Nabi SA, Moharam NM, Abou El-Khair MS. The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders. Menoufia Med J 2017;30:727-33

How to cite this URL:
El-Meshad GM, Abd El-Nabi SA, Moharam NM, Abou El-Khair MS. The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders. Menoufia Med J [serial online] 2017 [cited 2020 Jun 6];30:727-33. Available from: http://www.mmj.eg.net/text.asp?2017/30/3/727/218255


  Introduction Top


Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by impaired social communication and social interaction accompanied by atypical patterns of behavior and interest. As defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-V), ASD is differentiated from other developmental disorders by significant impairments in social interaction and communication, along with restrictive, repetitive, and stereotypical behaviors and activities [1].

Children and young people with autism frequently experience a range of cognitive, learning, language, medical, emotional, and behavioral problems, including the following: a need for routine; difficulty in understanding other people, including their intentions, feelings, and perspectives; sleeping and eating disturbances; and mental health problems such as anxiety, depression, problems with attention, self-injurious behavior, and other challenging, sometimes aggressive behavior [2].

Bioelements play important roles in the central nervous system. The lack or excess of essential minerals and trace elements are known to cause a variety of health problems, and could contribute to the etiology of ASDs. Autistic infants appear in some cases to develop normally until age 1-3 years. Thereafter, sudden changes occur that indicate the presence of an ASD. Possible causes for this are toxic metal exposure in combination with an inadequate nutritional status [3].

Given the importance of zinc (Zn) and copper (Cu) metabolism for healthy neurological functioning and detoxification of heavy metals, including mercury (Hg), it is thought that these two trace elements contribute in the pathogenesis of ASDs [4].

Zn supports normal growth and development during pregnancy, childhood, and adolescence. Individuals who suffer from severe Zn deficiency can develop neuropsychological changes such as emotional instability, irritability, and depression [5]. Zn is also involved in glutamatergic transmission with short-term and long-term effects that may go in opposite directions – for example, it blocks N-methyl-d-aspartate receptors [6].

Cu toxicity has a powerful effect on the mind. Cu at toxic levels can affect the mind moderately or very severely [7]. Potential neurotoxic effects of Cu in excess quantities include depression, irritability, fear, nervousness, and learning and behavioral disorders [8].

Zn maintains a balance with Cu in the blood, wherein changes in these two trace elements tend to be inversely related. This can in large measure be explained as a consequence of cytokine regulation of the metabolism of the two elements, with the same cytokines causing enhancement of the cellular uptake of Zn and enhancement of the production of ceruloplasmin in the liver. A low plasma Zn concentration is nearly always associated with a high serum Cu concentration. According to published studies, the normal Zn-to-Cu ratio in children and adults is close to 1:1. It has been proposed that the plasma Zn/serum Cu ratio may be used as a rapid method of determining the functional state of the metallothionein system [4].

Lower Zn/Cu ratios may reflect total body Zn deficiency or accumulation of Zn-antagonistic toxic metals. It has been proposed that Hg toxicity may be a major cause of metallothionein dysfunction in children diagnosed with an ASD, which may be reflected in the Zn/Cu ratio [4].


  Patients and Methods Top


Our study was carried out in the Psychiatric and Neurology Clinic, Department of Psychiatric, Menoufia University, during the period from April 2015 to October 2015 and approved by the Ethics Committee of Menoufia Faculty of Medicine.

The present study was designed to be of a case–control type. It enrolled 40 children. Twenty patients (15 male and five female) with autism diagnosed using the DSM-IV-TR and the Childhood Autism Rating Scales (CARS) (with no other medical disease were included). Their ages ranged from 3 to 11 years with a mean of 6.6 ± 2.9 years, and they participated in this study after written consent from their parents was obtained.

The control group enrolled 20 apparently healthy children, matched to the patients' age and sex. All control cases were also clinically examined by the pediatricians to exclude the possibility that the controls could have any subclinical autistic features.

Inclusion criteria

Children aged below 16 years from the Pediatric and Psychiatric Outpatient Clinic of Menoufia University Hospital suffering from ASD were included in the study. Inclusion criteria were as follows: no previous use of dimercaptosuccinic acid or other prescription chelators; no anemia or current treatment for iron deficiency anemia; no liver or kidney disease; well-hydrated; and receiving adequate daily intake of water.

Exclusion criteria

Exclusion criteria were as follows: presence of other neurodevelopmental disorders sharing common features (differential diagnosis, e.g., mental retardation); abnormal liver and renal function; nutritional disturbances; and being on medications that affect serum Zn (e.g., captopril) and plasma Cu level (e.g., phenobarbital).

All studied patients were subjected to the following: thorough history taking; clinical examination with special emphasis on neurological examination; diagnosis of autism using DSM-IV-TR criteria of autism [9]; and intelligence quotient (IQ) assessment using the Stanford − Binet Intelligence Scale [10] using the Arabic form translated by Melekah [11] (for children from 3 to 5 years of age) and the Wechsler Intelligence Scale for Children [12] using Arabic form translated by Melekah and Esmail [13] (for children from 5 to 15 years of age). Assessment of the severity of autistic symptoms was performed using the CARS. This scale is used to observe and subjectively rate 15 items [14], using Arabic form translated by Mariam Nour Eldeen. Routine investigations included the following: complete blood picture, and renal and liver function test to exclude other disease; assessment of plasma Zn level (normal level 63.8–110 g/dl) and serum Cu (normal level70–153 g/dl); and calculation of plasma Zn/serum Cu ratio. The normal Zn-to-Cu ratio in children and adults is close to 1:1 [4].


  Results Top


There were 20 patients, 15 (75%) male and five (25%) female. Their ages ranged from 3 to 11 years, with a mean age of 6.6 ± 2.9 years. Demographic characteristics of ASD and normal cases are shown in [Table 1]. In the current study, 75% of patients were male and 25% were female, with a ratio of 3: 1. Two of 20 patients had a family history of ASD, and three patients were of consanguineous marriage.
Table 1: Demographic characteristics of the studied groups

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Results showed no statistically significant difference between cases and controls as regards maternal age at the time of pregnancy (P = 0.6). Moreover, there was no statistically significant difference between cases and controls as regards antenatal risk factors (P = 0.9). There was a statistically significant difference between cases and controls as regards maternal Zn supplementation (P = 0.02).

The results also showed no statistically significant difference between cases and controls as regards birth weight (P = 0.5). No statistically significant difference was found between cases and controls as regards postnatal complication (P = 0.8). No statistically significant difference was found between cases and controls as regards type of feeding (P = 0.8).

Our results showed that there was a highly statistically significant difference between cases and controls as regards comorbidities [epilepsy and gastrointestinal tract (GIT) symptoms] (P = 0.001). An overall 30% of autistic children had epileptic focus in electroencephalograph, with and without a history of convulsions [Table 2].
Table 2: Electroencephalograph changes among autistic children and controls

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There was a highly statistically significant difference between cases and controls as regards IQ (P = 0.001) [Table 3].
Table 3: Intelligence quotient of the studied groups

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The results indicated that plasma Zn is significantly lower in patients than in controls (P < 0.001) as the mean Zn level in children with autism was 68.7 ± 26.4 μg/dl compared with 94.7 ± 11.9 μg/dl in controls [Table 4].
Table 4: Plasma zinc, serum copper, and plasma zinc/serum copper ratio of the studied groups

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Serum Cu was significantly higher in patients than in controls (P = 0.001) as the mean Cu level in children with autism was 151.6 ± 54.6 μg/dl compared with 105.4 ± 16.1 μg/dl in controls [Table 4].

Accordingly, the mean Zn/Cu was significantly (P < 0.001) lower in children with ASD compared with normal cases as the mean Zn/Cu level was 0.62 ± 0.2, which was below the 0.81 cutoff of the lowest 2.5% of healthy children [Table 4].

Zn/Cu decreased with increasing severity of ASD as defined by the CARS score [Table 5]. There was a significant negative association between Zn/Cu and CARS scores (r = -0.349 and P = 0.008). There was a positive correlation between age and Zn/Cu ratio (P = 0.049). There was no correlation between Zn/Cu and BMI (P > 0.05) [Table 5]. Zn/Cu ratio decreased with increasing severity of ASD as defined by the CARS score [Table 6].
Table 5: Spearman's correlation coefficient (r) between age, body mass index, sex, and zinc/copper ratio

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Table 6: Spearman's correlation coefficient (r) between Childhood Autism Rating Scales and zinc/copper ratio

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Our study showed that Zn/Cu correlates negatively with expressive language, receptive language, focus attention, hyperactivity, fine motor skills, gross motor skills, and tip toeing in autistic children (P < 0.005) [Table 7].
Table 7: Spearman's correlation coefficient (r) between selected symptom severity in autistic children and zinc/copper ratio

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On the basis of the receiver operating characteristic (ROC) curve, the optimal cutoff value of serum levels of Zn/Cu as an indicator for the diagnosis of autism was projected to be 0.81, which yielded a sensitivity of 85% and a specificity of 85%; the area under the curve was 0.93, negative predictive value was 85%, and positive predictive value was 85% [Figure 1] and [Table 8].
Figure 1: Scatter diagram showing the relation between age and plasma zinc serum copper ratio. ROC, receiver operating characteristic.

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Table 8: The receiver operating characteristic curve

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  Discussion Top


Our study was conducted on 40 autistic children and healthy sex-matched and age-matched controls. The mean age was 6.6 ± 2.9 years; 75% of patients were male and 25% were female, with a ratio of 3:1.

Sex differences in ASD occurrence may suggest a female protective effect. Clinically identified girls with ASD carry a higher load of deleterious genetic variants compared with boys and may have a higher threshold for the impact of the multifactorial array of genetic and environmental factors thought to be responsible for ASD [15].

In this study, there were five (20%) mothers with a history of Zn supplementation and fifteen with no history of Zn supplementation who only received iron formula. In controls, there was no history of Zn supplementation, only received iron formula, and hence there was a statistically significant difference between cases and controls as regards maternal Zn supplementation during pregnancy in autistic mothers and controls.

A study by Grabrucker et al. [16] stated that maternal Zn status is the focus as a possible environmental factor in the etiology of ASD. Thus, maintaining adequate Zn status during pregnancy might be a promising approach to prevent cognitive and neurobehavioral deficits later in life.

In our study, two (10%) cases were of low birth weight, and 18 (90%) cases were of average birth weight, and hence there was no statistically significant difference between cases and controls as regards birth weight (P = 0.5). This is in accordance with the findings of Fatma-Alzahraa et al. [17], who showed that LBW is probably an independent risk factor associated with the development of autism.

In this study, two cases had neonatal jaundice, another two were exposed to infection, and 15 cases had no history of postnatal complications. Hence, there was no statistically significant difference between cases and controls as regards postnatal complication (P = 0.8). This is in contrast to the findings of Kolevzon et al. [18], who showed that history of neonatal jaundice was statistically significantly increased in autistic patients (P = 0.000).

Among our autistic children, there were five (25%) cases with epilepsy, another five (25%) with GIT problems, and ten (50%) cases with no comorbidities. Hence, there was a highly statistical difference between cases and controls (epilepsy and GIT symptoms) (P = 0.001).

A study conducted by Schieve et al. [19] stated that autistic children were seven times more likely to have experienced gastrointestinal problems compared with typical controls.

In 85% of our patients the condition presented with delayed speech, in 90% with stereotyped behavior, in 90% with loss of eye contact, and in 95% with delayed motor development. Noens et al. [20] reported that about a third to a half of individuals with autism do not develop enough natural speech to meet their daily communication needs. In our patients, 95% had delay in motor development. This is in accordance with the findings of Esposito and Venuti [21], who said that ASD patients showed a range of gross motor problems, including delays in motor milestones, abnormal muscle tone, abnormal reflexes, and postural asymmetries.

In the current study, 30% of autistic children had epileptic focus in electroencephalograph, with and without a history of convulsions. This is in accordance with the findings of Kagan-Kushnir et al. [22], who found that seizures are common in ASD, occurring in ~20–30% of patients.

In our study, all autistic children (100%) had lower IQ compared with controls and all in the range of 22–71. This is nearly similar to a study by Stern [23], who stated that individuals with autism have significant levels of intellectual disability, defined as an IQ below 52.

Bioelements play important roles in the central nervous system. The lack or excess of essential minerals and trace elements are known to cause a variety of health problems, and could contribute to the etiology of ASDs [3]. Autistic children have a higher body burden of toxic metals compared with neurotypical controls [24].

Given the importance of Zn and Cu metabolism for healthy neurological functioning and detoxification of heavy metals, including Hg, it is thought that these two trace elements may contribute in the pathogenesis of ASDs [6].

In the current study, plasma Zn is statistically lower in patients than in controls (P < 0.001) as the mean Zn level of children with autism was 68.7 ± 26.4 μg/dl compared with 94.7 ± 11.9 μg/dl in controls. There was a highly statistically significant difference between cases and controls as regards plasma Zn (P = 0.001). This is in agreement with the findings of Faber et al. [4], who stated that the frequency of Zn deficiency is high in children diagnosed with ASD, and a study by Lakshmi Priya and Geetha [7], in which a significant variation was found for Zn in both hair and nails of low-functioning autism group children when compared with a control group and other study groups.

Cu is a trace element present in all tissues and is required for cellular respiration, peptide amidation, neurotransmitter biosynthesis, pigment formation, and connective tissue strength, and is a cofactor for numerous enzymes and plays an important role in central nervous system development. Cu toxicity has a powerful effect on the mind. Depending on the severity of the toxicity and the susceptibility of the person, Cu at toxic levels can affect the mind moderately or very severely [7].

In the current study, serum Cu was statistically higher in patients than in controls (P = 0.001) as the mean Cu level of children with autism was 151.6 ± 54.6 μg/dl compared with 105.4 ± 16.1 μg/dl in controls. This is in agreement with a study by Russo and deVito [25], who stated that autistic children have significantly elevated plasma levels of Cu (P = 0.0133).

In the current study, the plasma Zn/serum Cu ratio was statistically lower in patients than in controls (P < 0.001) as the mean Zn/Cu level was 0.62 ± 0.2, which was below the 0.81 cutoff of the lowest 2.5% of healthy children. Similarly, another study was carried out by Faber et al. [4], who found that the mean Zn/Cu was 0.608, which was below the 0.7 cutoff of the lowest 2.5% of healthy children.

In our study, there was a correlation between age and Zn/Cu ratio (P = 0.049). This is in contrast to the findings of Li et al. [26], who stated that there was no correlation between Zn/Cu and age. There was no relation between Zn/Cu ratio and BMI. This is in accordance with the findings of Li et al. [26], who stated that there was no correlation between Zn/Cu and sex, and BMI (P > 0.05).

In our study, there was a negative correlation between CARS and Zn/Cu ratio (r=-0.349 and P = 0.008). Thus, Zn/Cu decreased with increasing severity of ASD as defined by the CARS score. This is in accordance with the study by Adam et al. [27], who found that children with autism have higher average levels of several toxic metals, and levels of several toxic metals are associated strongly with variations in the severity of autism.

Our study shows that Zn/Cu correlates negatively with selected symptom severity in autistic children, and hence it is tempting to suggest that Zn/Cu could be used as a biomarker for diagnosis of autism, as Cu and Zn levels are altered in many other disease states and nutritional deficiencies. There was a negative correlation between Cu/Zn and expressive language, receptive language, focus attention, hyperactivity, fine motor skills, gross motor skills, and tip toeing.

This is in accordance with the findings of Russo et al. [28]. We found a correlation between Cu/Zn and expressive language (r = 0.3, n = 45, and P = 0.05), receptive language (r = 0.4, n = 43, and P = 0.01), focus attention (r = 0.23, n = 84, and P = 0.03), hyperactivity (r = 0.3, n = 79, and P = 0.01), fine motor skills (r = 0.32, n = 74, and P = 0.004), gross motor skills (r = 0.41, n = 68, and P = 0.0004), and tip toeing (r = 0.3, n = 71, and P = 0.03).

On the basis of the ROC curve, the optimal cutoff value of serum levels of Zn/Cu as an indicator for an auxiliary diagnosis of autism was projected to be 0.81, which yielded a sensitivity of 85% and a specificity of 85%; the area under the curve was 0.93. Thus, on the basis of the ROC curve, we consider that the Zn/Cu ratio could be used as an indicator of ASD. This is in accordance with the findings of Li et al. [26], who stated that, on the basis of the ROC curve, the optimal cutoff value of serum levels of Zn/Cu as an indicator for an auxiliary diagnosis of autism was projected to be 0.665, which yielded a sensitivity of 90.0% and a specificity of 91.7%; the area under the curve was 0.968 (95% confidence interval, 0.943–0.993).


  Conclusion Top


These results suggested an association between serum levels of Zn and Cu and ASD among our patients, and the Zn/Cu ratio could be considered a biomarker of ASD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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