Alternative Medicine Review 2010 (Apr); 15 (1): 15-32 ~ FULL TEXT
James Jeffrey Bradstreet, MD, MD(H), FAAFP; Scott Smith, PA;
Matthew Baral, ND; Daniel A. Rossignol, MD, FAAFP
International Child Development Resource Center,
Melbourne, FL 32934, USA.
Autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD) are common and complex neurodevelopmental conditions. Diagnostic criteria for these conditions have traditionally relied solely on behavioral
criteria without consideration for potential biomedical underpinnings. Newer evidence, however, reveals that ASDs
are associated with: oxidative stress; decreased methylation capacity; limited production of glutathione; mitochondrial
dysfunction; intestinal dysbiosis; increased toxic metal burden; immune dysregulation, characterized by a unique inflammatory bowel disease and immune activation of neuroglial cells; and ongoing brain hypoperfusion. Many of these same
problems are common features in children with ADHD. These medical conditions, whether co-morbidities or etiopathogenic,
would be expected to have synergistically negative effects on the development, cognition, focus, and attention of affected
children. It is likely these biological abnormalities contribute significantly to the behavioral symptoms intrinsic in these
diagnoses. However, treatment for these underlying medical disorders is clinically justified, even if no clear immediate
behavioral improvements are observed. This article reviews the medical literature and discusses the authors’ clinical
experience using various biomarkers for measuring oxidative stress, methylation capacity and transsulfuration, immune
function, gastrointestinal problems, and toxic metal burden. These biomarkers provide useful guides for selection, efficacy,
and sufficiency of biomedical interventions. The use of these biomarkers is of great importance in young children with
ADHD or individuals of any age with ASD, because typically they cannot adequately communicate regarding their
symptoms. (Altern Med Rev 2010;15(1):15-32)
Several abnormalities described in children with ADHD and ASD that can be screened with simple laboratory tests are summarized in Table 2.
CBC: A complete blood count (CBC) with differential can be performed. Abnormalities
described in some children with ASD include a high blood monocyte count  and abnormal lymphocyte function. [50-53] The CBC can also provide insights into allergies, anemia, and platelet counts. Platelet elevation, a nonspecific marker of immune activation, were observed in ASD and were responsive to biomedical intervention. 
CMP: A comprehensive metabolic panel (CMP) that includes liver and kidney testing is helpful.
High albumin has been described in some children with ASD.  Elevations in transaminases can be associated with mitochondrial disorders and, along with other markers, may support the need for skin or muscle biopsy for a
more definitive diagnosis. [55, 56] Determining renal and hepatic function prior to intervention with
medications represents a reasonable clinical protocol.
Magnesium: Magnesium (Mg) deficiency, which can be measured by any standard laboratory,
occurs in up to 95 percent of children with ADHD.  In a six-month, controlled study of 75 children with ADHD and magnesium deficiency (documented by low serum and red blood cell [RBC] magnesium) who all received standard pharmacological treatments for ADHD, a significant decrease in hyperactivity was observed with the addition of oral magnesium (200 mg/day) in 50 children compared to the 25 children who did not receive magnesium (p<0.05).  In a six-month, controlled study of 33 children with ASD, the use of vitamin B6 (0.6 mg/kg/day) and magnesium (6 mg/kg/day) led to a significant reduction of autistic symptoms in 70 percent of the children (p<0.0001), including improvements in social interaction, communication, and stereotypies; no adverse effects were observed. When the B6/Mg treatment was stopped the undesired behavior
returned within several weeks. 
Zinc: Zinc can be measured by any standard laboratory. In one study of 48 children with
ADHD and 45 typically developing children, mean serum zinc levels were significantly lower in the ADHD group (p<0.001).  Other investigators studied a group of 48 children with ADHD and observed that lower serum zinc levels correlated with parent and teacher rankings of inattention (p=0.004 for both).  In a controlled study of 45 autistic children compared to 41 typically developing children, plasma and RBC zinc levels were significantly lower in the autism group (p<0.05). 
Other minerals: One study reported that children with ASD and pica had lower hair
chromium.  Low hair iodine and lithium levels have also been described in some children with ASD.  A study of 20 children with autism and 15 typically developing children reported significantly lower RBC selenium (p<0.0006) in the autism group.  A reasonable method to determine mineral content is to assess packed red blood cell (PRBC) element concentrations, a technique that has been evaluated in the pediatric population. 
Iron: Iron deficiency appears to be relatively common in ADHD;  serum ferritin is low in
many children with ADHD compared to typically developing children. [67,68] Iron deficiency characterized by low serum ferritin is also observed in many children with ASD. [69,70] In a randomized, double-blind, placebo-controlled study of 23 ADHD children with serum ferritin levels less than 30 ng/mL, supplementation with ferrous sulfate (80 mg/day) over a 12-week period was well-tolerated and significantly improved ADHD symptoms (p<0.008) compared to no improvements in the placebo group.  In an eight-week, open-label study of 33 children with ASD, supplementation with iron (6 mg/kg/day) significantly improved sleep and increased mean serum ferritin levels. The investigators suggested that children with ASD should be routinely screened for iron deficiency and recommended obtaining serum ferritin and iron levels. 
Hypothyroidism: Hypothyroidism has been described in some children with ASD  and
ADHD;  therefore, screening for hypothyroidism with a blood test for thyroid-stimulating hormone is recommended. Normal ranges for children vary among laboratories. It is not unusual to see two standard deviations signify a 10-fold difference in TSH levels. TSH levels at the mean or lower are considered optimal by these authors. Elevated TSH may be a reflection of iodine deficiency, an easily corrected nutritional problem.
Oxidative Stress Biomarkers
Oxidative stress is a common finding in many children with ASD [12,13,47] and ADHD. [31-33] Glutathione is the primary intracellular antioxidant and has been shown to limit mercury-induced neurotoxicity.  Impaired glutathione production contributes to oxidative stress, which may delay the clearance of heavy metals and certain xenobiotics.  In two prospective studies, over 50 percent of children with ASD had significantly lower plasma levels of glutathione and cysteine (p<0.001 for both) compared to typically developing children. [12,14] James et al hypothesized that because of these findings, “autistic children would be expected to have difficulty resisting infection, resolving inflammation, and detoxifying environmental contaminants.”  The following biomarkers, summarized in Table 3, can be measured to assess the level of oxidative stress.
Reduced glutathione (GSH) and oxidized glutathione (GSSG):  An Internet search of
laboratory providers for this special testing found several commercially available companies capable of measuring these valuable markers. Measuring total glutathione along with GSSG and/or GSH will help determine the patient’s oxidation status.
Levels of major antioxidant proteins in the serum (standard blood tests): Transferrin (an
iron-binding protein) and ceruloplasmin (a copper-binding protein) are antioxidant proteins significantly decreased in children with ASD compared to typically developing children. [13,81] One study reported that lower levels of these proteins were associated with regression and loss of previously acquired language skills in children with ASD.  Results of such testing should be viewed with caution, however, since a variety of conditions influence the levels of either protein, making interpretation challenging.
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