This question comes up a lot online: "What are the optimal reference ranges for thyroid hormone labs in children?" I hope this post serves to help parents and physicians understand optimal reference ranges for children versus reference ranges reported on actual lab results. This is an important topic as thyroid hormone is crucial for brain and global development of infants and children.

Unfortunately, there are no national or international standards for reference ranges that labs use. This has resulted in sometimes huge variations in reference ranges used by different labs.  Ultimately, a well-studied physician should have their own reference ranges that they use when evaluating labs.

The six most important labs to obtain when assessing thyroid function, regardless of the age of the patient, are:

1. TSH
2. free T4
3. free T3
4. reverse T3
5. TPO
6. TgAb

There are others but these are values that assess direct thyroid hormone status. The other labs that are pertinent to thyroid hormone function are CBC, ferritin, zinc, copper and vitamin D. I'll start by reviewing in very simple terms the thyroid hormone cascade.

The most important message to take away from this is that the thyroid hormone process within the body is complicated and involves many steps that include proper pituitary function, thyroid gland function, deiodinase enzyme function, cell receptors and thyroid hormone receptors within each cell of the body.  A problem in any of these steps can result in hypothyroidism.

​Given the negative feedback loop that occurs between TSH and T4, endocrinologists have been using TSH levels only to assess the health of the very complicated thyroid hormone process for their patients. This has resulted in many patients who still experience symptoms of hypothyroidism but are told by their doctor that they don't have hypothyroidism. The result of this for an adult is often continued fatigue, depression, weight gain, dry skin and many other symptoms. Given the critical role thyroid hormone plays in childhood development at key stages that can't be revisited, this same incomplete assessment can result in irreversible lack of optimal brain development. For a thorough review of the important role thyroid hormone plays in brain development please read "Thyroid Hormones in Brain Development and Function" by Juan Bernal, M.D. Ph.D.

As it turns out several studies do exist supporting that the current practice of using TSH only to assess thyroid hormone function is missing a lot of patients with hypothyroidism, including children. One such study was conducted in 2005 by researchers at Athens University School of Medicine (Koutras, 2005). They tested TSH, T4 and T3 levels in 85 patients with hypothyrodism who were taking T4-only medication. They found that these patients had lower T3 levels compared to normal, non-hypothyroid subjects. They concluded that hypothyroid patients may benefit from co-administration of T3 and T4 medication. They also concluded, "TSH levels used to monitor substitution, mostly regulated by intracellular T3 in the pituitary, may not be such a good indicator of adequate thyroid hormone action in all tissues. " In 2015 a team of physicians collaborated to write "Homeostatic Control of the Thyroid–Pituitary Axis: Perspectives for Diagnosis and Treatment".  They suggest that the use of TSH be "scaled back" and highlight the importance of T3 hormone levels.

​The most important work being done to support the need to use more in-depth labs and assessment when testing patients for hypothyroidism is Dr. Antonio Bianco. The website for his lab is Deiodinase.org.  His lab is doing extensive and valuable work investigating the important role that local cellular control of thyroid hormone plays in the thyroid status of patients. This website contains a wealth of knowledge regarding deiodinase enzymes and I highly recommend Endocrinologists start studying his work.

Although the role TSH levels play in thyroid hormone assessment should be downplayed, an optimal reference range should still be discussed. Many functional medical doctors agree that an optimal reference range for a test result is quite different than reference ranges that have been established by labs.  These reference ranges may be capturing lab values for patients with undiagnosed pathology. The optimal reference range for TSH is generally accepted to be 1.0-2.5 mIU/L.  In 2015 the American Association of Clinical Chemistry published "Thyroid-Stimulating Hormone" in which they state:

As well, researchers in the UK refer to a normal TSH as <2 mIU/L in "Pitfalls in the measurement and interpretation of thyroid function test".

The optimal reference range for TSH in newborns, infants and children varies from those of adults. In addition, there are definite differences in optimal free T4 and free T3 levels in children. The most comprehensive anaylsis of thyroid hormone tests of pediatric patients was done in 2008 (Kapelari, 2008). Researchers analyzed medical records of 414 patients.  Patients were grouped into age ranges of 1 day to 1 month, 1 – 12 months, and 1 – 5, 6 – 10, 11 – 14, and 15 – 18 years, respectively. They state in their conclusion, "Our results corroborate those of previous studies showing that thyroid hormone levels change markedly during childhood, and that adult reference intervals are not universally applicable to children." The images below are graphs from this study displaying their findings. The darkest black line in the graphs represents the 50th percentile (median) lab result.

The conversion of pmol/L to pg/mL, the unit of measurement most often used in the US for free T3, uses the conversion factor of 1.536. The pmol/L number is divided by 1.536 to get pg/mL.  The conversion of pmol/L to ng/dL, the unit of measurement most often used in the US for free T4, uses the conversion factor of 12.9. The pmol/L number is divided by 12.9 to get ng/dL.

The results from Kapelari's study are converted to US units of measurement and summarized in Table 1.

A reference range for reverse T3 in infants and children has not yet been established nor has it adequately been studied. However, some studies do exist. Researchers at UCLA studied levels of T4, T3 and reverse T3 in neonates from 1-30 days old. They found that "high serum rT3 concentration in the newborn becomes comparable to that in the normal adult by 9-11 days of neonatal life." (Chopra, 1975) The same dramatic decrease in reverse T3 in newborns was reported by Dr. Brown and Feingold in 2010 as seen in Image 7. (Brown, 2010) A striking increase in T3 levels after birth was noted by both studies as well. Reference range for reverse T3 in adults has been established to be 10-24 ng/dL. (Endocrine Society Laboratory Reference Ranges) Unfortunately, until further studies are conducted the only information available today regarding reverse T3 in infants is to use that of adults.  

It's of utmost importance to assess signs and symptoms of hypothyroidism in infants and children in addition to lab results when determining their thyroid hormone status and whether thyroid hormone supplementation is warranted or not.  Those signs and symptoms include:

• Dull look
• Puffy face
• Thick, protruding tongue
• Choking episodes
• Constipation
• Dry, brittle hair
• Jaundice
• Low muscle tone (floppy infant)
• Low hairline
• Poor feeding
• Short height
• Sleepiness
• Sluggishness
• Slow growth
• Hoarse-sounding cry or voice
• Short arms and legs
• Very large soft spots on the skull (fontanelles)
• Wide hands with short fingers

Thyroid antibodies should always be checked when assessing thyroid status given the high prevalence of autoimmune induced hypothyroidism. Naturally, these antibodies ideally should be as low as possible. Once again reference ranges vary widely from lab to lab.  The Endocrine Society has determined the reference range for thyroid antibodies to be:

• TPO (Thyroperoxidase) - < 2.0 IU/mL
• TgAb (Thyroglobulin antibodies) - < 4.0 IU/mL

Functional medical physicians are also taught that TPO up to 15 IU/mL is normal. Reversing autoimmune hypothyroidism and lowering these antibodies is possible. The treatment for doing so is outside the scope of this article. I highly recommend working with a physician who is trained in treating the root cause of autoimmunity if you or a loved one has elevated thyroid antibodies.

In short, hypothyroidism should not be missed in any infant or child given the important role thyroid hormone plays in the health and development of children. Signs and symptoms should never be ignored and a complete and thorough check of all thyroid hormone levels should be conducted.

**Please do not write comments that include your child's specific lab values asking for medical advise. We will not be able to give medical advise based on lab values alone and cannot give medical advise in this format. These comments will not be approved for posting. Feel free to contact the office to make an appointment if you would like our help.

Here are some tips to safely manage a fever:

1. Hydrate - encourage drinking of homemade electrolyte replacement drink that can be made into popsicles as well. 
2. Enhance a fever if needed with chamomile, ginger and yarrow tea.
3. Monitor the temperature frequently, especially in a child.  The most accurate way to obtain the temperature in a young child is rectally, but other means can be used as well.
4. Rest - No matter how busy you are you must conserve energy and stay in bed. To keep young children still try putting on their favorite video (an exception to limiting screen time for children).  Often the aches and malaise that come with the fever don't allow for much activity.
5. Observe for signs of dehydration. Babies should urinate at least once every 6 hours, children and adults should urinate at least once every 8-12 hours. Sunken eyes, dry mouth, dark urine, little to no tears when crying, lethargy, dizziness and even confusion are all signs of dehydration.

If your child experiences a febrile seizure:

• Seek medical help immediately, not tomorrow morning. Call 911.
• While waiting for emergency help, keep your child upright and make sure their airway stays open and they are able to breathe.  Watch for changes in your child's breathing and/or color.
• Stay with your child and speak reassuringly.
• Clear the area around your child to prevent injury. Do not try to hold your child down. Restraining a thrashing child can cause additional injury. Try placing a soft pillow or blanket under your child's head. Loosen clothing to prevent injury and ease discomfort. 
• Do not try to force anything into your child's mouth. You might cause choking, or suffer a bite yourself.
• If vomiting occurs, turn your child's head to the side so that there is no risk of your child choking on inhaled vomit. If possible, keep your child's whole body turned on the side as well.

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To cool a really high fever naturally and help a child or adult with a fever try a wet sheet wrap.  For a small child a pillow case can be used.  Get the sheet or pillow case soaking wet with cold water.  Be sure to wring it out well so that it isn't dripping wet.  Wrap the child very quickly in the sheet or pillow case and cover the wet sheet with a warm blanket, preferably wool.  It's most important to wrap the torso, so their arms can be free if they aren't comfortable being wrapped tightly.  They may object at first to the cold wet sheet, but will soon be comforted by the cooling sensation.  They will most likely fall asleep shortly after being wrapped up.  Let them sleep as long as they can in the wrap; two hours or more is best.  If they will tolerate it all night long that is ideal.  For an adult lay the dry blanket on the bed and place the wet sheet on top of that.  Lay down on the wet sheet and wrap yourself up snugly or have someone help you.  Again, sleep in this for as long as you can tolerate it, preferably overnight.  The sheet will be dry in the morning.  This technique can be used to help "break" a fever. ​​

Those are some strong words that likely got your attention whether you're a parent or a physician.  Medical neglect typically refers to a parent who neglects to seek out professional help for their child who is in obvious need of medical attention. This is not the medical neglect to which I'm referring. I would like to broaden that term to include physicians. That's right. Physicians who took an oath to "do no harm" now work in a healthcare system that doesn't give them enough time to always fully help their patients. When the writing of a prescription replaces the doctor's role to get to the root cause of the problem and the patient can as a result experience negative side effects from an unnecessary prescription then this patient has experienced more harm than good from that appointment. The average time doctors spend with their patients has been estimated to range anywhere from seven to fifteen minutes.(1, 2)  In some cases those fifteen minute appointments are for a new patient. How can a physician possibly review everything necessary in order to truly help their patients in this amount of time? I spend two hours (sometimes up to three hours if I have to) with a new patient. Follow up appointments are no shorter than thirty minutes and those are often rushed with everything that needs to be discussed. 

I'll discuss here how this current medical system impacts children with Down syndrome and autism, but this extends to children with ADD/ADHD, anxiety, OCD, seizures, Sensory Processing Disorders and others.

The correct or polite term for this is actually "diagnostic overshadowing". This term was first used in 1982 by Dr. Steven Reiss a professor and researcher in clinical psychology at Ohio State University. Dr. Reiss originally used the term in relation to those with mental illness. It's used today in reference to those with a learning disability as well. Diagnostic overshadowing is defined as leaving co-existing conditions undiagnosed and untreated once a diagnosis is made of a major condition, such as autism or Down syndrome. Children whose medical needs are being ignored simply because they are intellectually different are experiencing neglect of their medical needs. I call it like I see it. If you've ever heard a doctor say, "Well, that's normal for Down syndrome." or "That's expected in a child with autism." that child is experiencing diagnostic overshadowing or medical neglect as I see it.

It's ultimately not the physician's fault when they work in a system that doesn't allow them enough time with their patients or if they simply haven't been trained in functional medicine which addresses the true underlying causes of ill health.  However, when a parent reaches out for help by presenting a physician with information that can help their child, and then that physician dismisses the information and tells the parent that what their child is experiencing is normal and expected given their diagnosis THAT is medical neglect. One analogy would be if a patient had bone cancer and was experiencing pain and the doctors chose to not look for the cause of the pain because pain is expected in patients with bone cancer.  What if the pain is from a fracture that can be seen by an x-ray and helped with a simple cast? If this sounds preposterous to you then it should be equally absurd that developmental delay and cognitive issues in people with Down syndrome are dismissed as well.

Some may be reading this and saying, "But what about those who are more severely affected?".  I don't want to sugar coat it. Some children with Down syndrome and autism are more severely affected than others. However, these are the children and adults who most likely experienced medical neglect or diagnostic overshadowing during critical years of development that made the biggest impact on their health and cognition. If having an extra copy of chromosome 21 was the only thing that dictated the health and cognitive abilities of a person with Down syndrome how does one explain the large range of health and abilities in those with Down syndrome? Clearly their health and cognitive function must be impacted by more than just the extra chromosome.

​I'll give you an example of a patient.  I'll call her Mary in order to maintain anonymity and to give her a name instead of just calling her a "case".  Mary was two years old when her mother brought her to see me. When I greeted them in the waiting room for the first time I immediately could see that Mary was not well. She did not make any eye contact, made few to no sounds, was extremely congested and could only roll around on the floor like a three month old. Mary's mother was told, "Well, she has Down syndrome."  I can tell you right now that this was NOT "just Down syndrome."  I've worked with hundreds of children with Down syndrome who were able to walk, talk and were quite engaging at her age.

Mary was diagnosed at birth with having Down syndrome and was her mother's third child. Despite being told that children with Down syndrome typically can't breastfeed and that she shouldn't even try, her mother was able to get her to exclusively breastfeed successfully for her first six months of life. Unfortunately at her six month checkup her Pediatrician realized she hadn't been growing. His means of managing this was to recommend that the mother stop breastfeeding and switch to commercial, powdered, dairy-based formula so that they could measure exactly how much Mary was actually feeding.  Let's stop here.  I hope you see that this was mistake #1.  It has been well-established in medical literature that breast milk is best for babies.(4) One could argue that's it's even more important for a child with Down syndrome who is at greater risk for developmental delays and needs every advantage possible for optimal health. This physician chose to remove what was best for the child and ignore other possible causes of slow growth in children, one of which can be hypothyroidism which is very common in children with Down syndrome.

​Mary had symptoms of hypothyroidism since birth that included low muscle tone, low temperature and prolonged jaundice, among others. Her thyroid labs were not checked at six months old when her growth was seen as an issue. Soon after starting formula she was also started on solids. Reflux and severe constipation, going as long as two weeks without a bowel movement, quickly became a problem after these changes to her diet.  She was then put on Omeprazole at eight months old for the reflux. This is a medication that decreases acidity in the stomach and can lead to vitamin and mineral deficiencies. Studies show that dairy allergy is strongly linked to reflux in infants (5,6) and switching formula or finding a breast milk donor would have been the better choice.

Not long after being placed on Omeprazole she had what was interpreted as a seizure or infantile spasms. Sandifer's syndrome had not been ruled out. This is reflux that looks like a seizure and is under-recognized in the medical community. A short course of steroids was started to treat her "seizures" and was ineffective. Her seizure-like behavior/reflux was actually a sign that the Omeprazole was not working. Another sign that this medication was ineffective and that she was still experiencing reflux was her chronic upper respiratory congestion, a symptom of reflux. This congestion resulted in multiple rounds of antibiotics in her mere two years of life. Her adenoids were enlarged and removed at 18 months old after a sleep study was done that found moderate sleep apnea.  This exposed her to anesthetics which can be harmful in a child who is not able to properly detox them from the body. In addition her pain after surgery was managed by multiple doses of Tylenol which has been shown to reduce the activity of the enzyme glutathione reductase. (7) This enzyme functions in a necessary step in our body's internal anti-oxidant and detoxification system and is crtical for children with Down syndrome.

​Her extreme constipation and bloating resulted in a prescription for Miralax. It was advised that she take this daily for an extended period even though it's safety and use hasn't been studied in very young children. Many parents would be shocked to know, given how commonly Miralax is prescribed, that concerns over adverse side effects from it include seizures, tremors, tics, headache, anxiety, lethargy, sedation, aggression, rages, obsessive-compulsive behaviors including repetitive chewing and sucking, paranoia and mood swings." These side effects were discussed during the June 18, 2009 FDA Drug Safety Oversight Board meeting.(8)

​You can imagine my frustration and sadness hearing her story.  Misstep after misstep from well-intentioned, ill-informed doctors resulted in Mary's severe delay in development and probably contributed to much of her cognitive delays as well.  At one point during her appointment, when the mother went outside to get some paperwork from her car, I picked up Mary to put her on my exam table.  I looked at her closely and with great intention said, "We're going to get you back."  I knew there was a lot I could do to help but was also fearful of the amount of damage that had been done.

I won't go into great detail about her treatment plan as that's outside the scope of this article.  What I will say that I did was to treat her undiagnosed and untreated hypothyroidism, remove her from cow dairy formula and gave the mom some safe and very effective remedies for constipation, among other things.  At her follow up appointment two months later I got to meet Mary for what seemed like the first time.  She was alert, made eye contact (although infrequently), was able to sit up on her own for extended periods of time and she imitated me making some popping noises with my mouth. This was a huge leap in her development in only two months! We still have a lot of work to do to help Mary heal. Much of that work will be to heal her gut after the assault from dairy formula, Omeprazole, Miralax and antibiotics.  ​

​Mary's story is not unique.  This happens to hundreds and thousands of children with special needs who experience more visits to the doctor's office than other children. These visits often result in prescriptions that are causing more harm than good, not to mention the lack of addressing the root cause of their symptoms.  I recognize Mary's delays as being due to hypothyroidism and severe gastrointestinal dysbiosis NOT her having Down syndrome. Addressing hypothyroidism, gut dysbiosis and malabsorption are the biggest ways that children with Down syndrome and other special needs can be helped. Ignoring that environmental factors like mode of delivery, breastfeeding, diet, early exposure to antibiotics and other drugs that impact the microbiome have an even greater role on their health than that extra copy of chromosome 21 is the greatest medical tragedy that these children experience. Dr. Noel Mueller and his colleagues accurately stated "The infant microbiome plays an essential role in human health and its assembly is determined by maternal-offspring exchanges of microbiota. This process is affected by several practices, including Cesarean section (C-section), perinatal antibiotics, and formula feeding, that have been linked to increased risks of metabolic and immune diseases." in their 2015 review article.(9)  In addition, it's been well established that children with autism have a greater prevalence of gastrointestinal problems than their typical peers as outlined in "Gastrointestinal Symptoms in Autism Spectrum Disorder: A Meta-analysis". (10) Many believe, given the strong connection between the health of the gut and the health of the brain, that this may be a major causative factor of autism.
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The amount of research connecting the impact that our microbiome has on our overall health and especially our brain health is growing rapidly. Mayer, et al stated "the discovery and the explosive progress in the characterization of the gut microbiome have initiated a paradigm shift not only in medicine, but also in the basic and clinical domains of neuroscience." in their article "Gut Microbes and the Brain: Paradigm Shift in Neuroscience".(11) Children and adults with Down syndrome are not exempt from this information. They experience a higher rate of c-section births (12), lower rate of breastfeeding (13) and greater exposure to antibiotics.(14) These are the three things that have the greatest impact on the health of an infant's developing microbiome early in life that can impact their health into adulthood.(15)

Although much of this research is new it's imperative that Pediatricians and Family Physicians who are committed to helping all of their patients, including those with special needs, be current on this research. It takes, on average, 17 years for research to translate to policy and clinical practice. (16) We, as a global society, don't have that much time. 17 years is a childhood. The rate of autism is growing rapidly and these children will soon be adults.  A shift is greatly needed in the current paradigm of medical practice. This includes everything from the attitudes of physicians to the current structure of our healthcare system that only gives doctors 10 minutes with their patients.  I've outlined some steps below that I hope parents and physicians will take seriously.  We must each look deeply at our own current attitudes and ability to shift our thinking in order to do what's best for the child.  It's not about being right; it's about getting it right for these children and their families.  Never stop learning and searching for answers.  Many children today whose parents are working with doctors trained in looking for and treating the root cause of symptoms are experiencing significant healing, some even losing their diagnosis of autism.

Steps physicians can take to prevent this from happening:

1. See the patient as a person first.  Recognize that their diagnosis doesn't define them and doesn't always explain every health issue.
2. Listen to parents and see them as a partner in helping their child.
3. Be open to the idea that there's more that can be done to help children with special needs than medical school has taught most physicians.
4. Read up on the impact that gastrointestinal microbial dysbiosis can have on a person's health and cognition. (Brain Maker by Dr. David Perlmutter)
5. See the patient holistically and understand that improvements in overall health can lead to improvements in brain health and cognition. (Reversal of cognitive decline: A novel therapeutic program)
6. Study the symptoms of hypothyroidism and don't ignore them in any patient, especially those with Down syndrome. (Neonatal hypothyroidism, Hypothyroidism)
7. Gain an appreciation for epigenetics and understand that our health is not dictated by our genes alone.

Tips for parents to prevent medical neglect:

1. Don't ever let any physician use the excuse "that's just Down syndrome" (or whatever diagnosis your child has).
2. If your physician isn't willing to do the first three steps above then find another physician who is willing to do so.
3. Understand that your child's potential is much greater than has ever been thought possible and if your child doesn't seem to be reaching their fullest potential there could be an underlying medical reason outside of the extra chromosome or diagnosis. Here's an example of someone who's breaking stereotypes: All lives matter | Karen Gaffney | TEDxPortland

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Dr. Sidney Baker summarized it best in "Learning About Autism".

​No one is questioning the intentions of physicians.  Naturally, their intention when writing a prescription is to help their patient. Most physicians truly want to help their patients. In order to do so, however, some changes are needed in the way conventional physicians see their patients with special needs.  I highly recommend that all physicians who have patients with autism and Down syndrome read Dr. Baker's article I cited here. The attitude that he conveys applies not only to children with autism but to children with Down syndrome as well. Physician's should ask themselves, "Am I doing EVERYTHING possible to help my patient?". I ask myself this same question all the time.

I encourage parents to briefly share your child's story in the comments below if you've experienced this so that others can see how common this truly is.

Healthy polyphenols from food can be categorized into flavenoids and non-flavenoids (image 3).  Polyphenols are abundant micronutrients found in our diet.  They've been linked to preventing degenerative diseases like cardiovascular disease, cancer and dementia (1,2,3). Their exact mechanism of action isn't completely understood.  What is known is that they have anti-inflammatory and anti-oxidant properties (4,5,6).  

In addition to the above mentioned benefits polyphenols have been studied for their effect on those with Down syndrome.  These studies give some insight into the possibility that polyphenols have epigenetic properties and impact the expression of the DYRK1A gene, found on chromosome 21.  This gene codes for the enzyme Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A.  This enzyme plays a roll in cell proliferation (increase in number of cells) and brain development.  As with many genes, over-expression and under-expression of the same gene can be a problem.  Given that those with Down syndrome have an extra copy of chromosome 21 the over-expression of DYRK1A is considered to be a strong candidate gene for learning defects associated with Down syndrome (7).  

The polyphenol that has been most tested for it's impact on those with Down syndrome due to it's known ability to inhibit DYRK1A expression is EGCG (Epigallocatechin gallate).  Researchers in Spain tested EGCG in children with Down syndrome and found it "significantly reverses cognitive deficits in a pilot study in DS individuals with effects on memory recognition, working memory and quality of life" (8). EGCG has also been shown to play a role in preventing Alzheimer's disease which occurs in 100% of those with Down syndrome (9).

More evidence exists supporting the impact that polyphenols have on genetic expression.  In 2013 Pan reported, "Over the past few decades, polyphenols, which are widely present in foods such as fruits and vegetables, have been shown to exhibit a broad spectrum of biological activities for human health. Polyphenols reverse adverse epigenetic regulation by altering DNA methylation and histone modification, and they modulate microRNA expression or directly interact with enzymes that result in the reactivation of silenced tumor suppressor genes or the inactivation of oncogenes."(10). Susanne Henning and her team at the UCLA School of Medicine also reported in 2013 that EGCG does, in fact, inhibit DNA methylation (11). Cancer ican be prevented by inhibiting DNA methylation because methylation can block the expression os tumor suppressor genes.  You can read more about DNA Methylation in by blog post here.

Another popular polyphenol that has a lot of research supporting it's use in neurodegenerative diseases is resveratrol (12).  Resveratrol is found in red grapes and Japanese knotweed. It, too, has been tested in those with Down syndrome, but studies are few.  Researchers in Italy have reported "the natural polyphenol resveratrol, which displays a neuroprotective action in various human diseases but never tested in DS, restores oxidative phosphorylation efficiency and mitochondrial biogenesis."(13).  Many parents have started using resveratrol in their children with Down syndrome and are reporting immediate and clear increases in speech and cognition when starting resveratrol.  Unfortunately, no published studies exist currently to support this.

Ultimately, the multiple ways that dietary polyphenols positively impact human health cannot be denied.  But, is there a point that they can cause any harm or do they have any side effects? The answer is, "Yes".

Phenols need to be processed, metabolized and modified within the body in order to work properly.  The main enzyme that's involved in the processing of phenols is phenol sulfotransferase (PST).  This enzyme is heavily dependent on sulfur as you might be able to tell from it's name.  So, the intersection of sulfation and phenol metabolism within the body is an important one.  I'll start by talking about sulfation.

You can see from these steps that if sulfur in the diet, sulfur absorption, B6 or molybdenum are deficient this can create problems in a wide arrary of biological activities, including the activity of the PST enzyme.  When this enzyme is not supported by adequate levels of sulfate it creates an overload of phenols that are not processed properly.  Unfortunately there is no test for this.  It's based solely on symptoms, however there are some labs that can give clues to an impaired sulfation system. 

Some clues to sulfation issues with in the body on labs can be a high taurine in the urine.  This is termed "taurine wasting".  This is the body's means of removing toxic sulfite when it isn't converted properly to sulfate. The body "chooses" taurine because it is high in sulfur.  This creates an actual taurne deficiency. Supporting the SUOX enzyme with molybdenum can help to rememdy this.  In fact, researchers in Germany found a 20-fold increase in urinary taurine levels in those who were deficient in molybdenum (14). If B6 deficiency is seen on an organic acid test in an elevated xanthuernic acid, kynurenic/quinolinic acid then supplementing with B6 can also help support the CDO enzyme.

In addition to phenol overload, parents using polyphenols for their children should also know that phenols are strong infibitors of iron absorption (15) which can already be a problem for some children, especially those with gastrointestinal disorders. I often recommend to not start EGCG or resveratrol until ferritin is closer to 40 ng/mL or at least to take an iron supplement when needed, but as far from taking the phenolic compound as possible (i.e., iron at bedtime and EGCG with breakfast). As well, EGCG inhibits the catechol-o-methyltransferase enzyme (COMT) that breaks down estrogen, epinephrine and norepinephrine (adrenalin) (16).  Parents should be mindful of a potential increase in adrenalin when using EGCG.

Lastly, there are some that may have a mutation in their PST enzyme (17), making it work more slowly despite sufficient sulfate.  It's been estimated in unpublished data by Dr. Rosemary Waring that approximately 80-90% of children with autism struggle with the function of this enzyme either because of low sulfate levels or because of a defect in this enzyme that detoxifies environmental toxins, food dyes, additives, some medications, phenols made by the body and phenols obtained in the diet.

The first step is to remove or greatly reduce all high phenol foods and supplements for at least 2 weeks to see if symtpoms improve.  If they do, avoiding high phenol foods and supplements does not have to last forever. The goal is to support the PST enzyme by increasing sulfate blood levels.  Because sulfate can be difficult to absorb in the GI tract using epsom salt baths with magnesium sulfate on a nightly basis is an excellent way to increase sulfate in the body.  As well, taking molybdenum, B6 and magnesium can also support the sulfation pathways.  

Click on the image below to open a printable pdf to refer to often during the 2 weeks of avoiding foods high in phenols:

In addition to the above steps there also is an enzyme that can be taken as a supplement that helps process phenols.  It's xylanase.  The products below have been used successfully by many parents when helping their children with phenol overload.  I don't recommend simply starting this enzyme.  Removing high phenol foods and supplements for two weeks is the first step to lower the phenol load within the body.  Then slowly introduce high phenol foods with one of these enzymes. Only after no reactions are seen should high phenol supplements like EGCG and resveratrol be reintroduced.

Ultimately, parents should know that just because a supplement or compound comes from nature does not mean that it doesn't have side effects, especially when given in higher doses than would be obtained from food as in the case of supplements.  The benefits from these compounds can be great when the child's body is ready for it and all necessary cofactors are in place for it to work optimally. We all want to ensure that our children are given supplements that are helping them and not causing harmful side effects.

​The process by which mitochondria make energy in the form of ATP is complicated but can be broken down into four basic steps:

1. Glycolysis
2. Pyruvate Oxidation
3. Citric Acid Cycle (Krebs Cycle or Tricarboxylic Acid Cycle - TCA)
4. Electron Transport Chain (Oxidative Phosphorylation)

I will focus on the steps that occur within the mitochondria only. Those are the Citric Acid Cycle and the Electron Transport Chain. These last two steps can only occur in the presence of sufficient amounts of oxygen. When oxygen levels are low, like in sleep apnea or during times of intense exercise when oxygen demand from muscles exceeds available oxygen, pyruvate cannot be shuttled into the mitochondria. Lactic acid fermentation is used instead which is much less efficient and generates only two ATP molecules.
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The following video reviews the basic steps in the Citric Acid Cycle. Keep in mind, this is a basic representation and there are many other factors that are involved.  You should also know that ubiquinone is CoQ10.

The NADH and FADH2 that are generated from the TCA carry their electrons to the electron transport chain where they are used in the final step to make energy as shown in the video below. Check out that cool ATP synthase complex at the end....like mini turbines in every cell!

All of these processes work together in what's called "Cellular Respiration", so named because it's how our cells use oxygen (image 2).

I made this "puzzle" years ago to use for my students (image 3) and still have it on my bookshelf. I used to have them print it, cut out all of the parts and put it together at home. They would receive an extra point on their exam if they sent me a photo of it assembled. Typically the students who found it fun and helpful really didn't need the extra point on their exam.

It's easy to see here how our bodies work like well-oiled machines when provided with everything it needs to function properly. For every one molecule of glucose the body is able to make approximately 35 molecules of ATP: two from glycolysis, one from the TCA and 32 from the electron transport chain. Sometimes it makes less when this process isn't working as efficiently.

If you're craving even more information on this topic, this chapter of the The Cell by Alberts B, Johnson A, Lewis J, et al. outlines these processes in much greater detail: The Mitochondrion.

The areas of highest mitochondrial activity, based on the rate of ubiquinone reduction and oxidation, are the heart, kidney and liver (1). As well, because the brain is the most metabolically active organ in the body it is vulnerable to disruptions in mitochondrial function. 

Most conventional medical doctors are not trained to recognize mitochondrial dysfunction. Research supporting mitochondrial dysfunction as a clinical entity is vast and growing. However, as is often the case, much of this research is not incorporated into every day medical practice.

Several researchers have reported a connection between mitochondrial dysfunction and autism (2,3,4). In addition, mitochondrial dysfunction in Down syndrome has been well-established (5). Many biomedical clinicians have already come to accept that mitochondrial dysfunction is something to look for and treat in children with autism and other special needs. As well, many parents are seeing notable improvements in their children's health and development when mitochondria dysfunction is detected and addressed.

Because so many organs and processes of the body are dependent on ATP and the mitochondria that makes it, symptoms can be vague and impact many organ systems.  These symptoms include:

• Low muscle tone
• Difficulty swallowing
• Failure to thrive
• Learning disability
• Fatigue
• Delayed gut motility
• Heat/cold intolerance
• Migraines
• Lactic acidosis
• Liver disease
• Immune system problems
• Heart problems
• Kidney problems
• Neurological problems
• Autonomic dysfunction

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You can see how easily a doctor might dismiss these symptoms as Chronic Fatigue Syndrome, Irritable Bowel Syndrome or no diagnosis is made and "there's nothing that can be done". Many times pharmaceutical drugs will be used that mask these symptoms yet never really help the patient nor address the root cause of the patient's problem.

What do mitochondria need in order to function properly?

All of the above steps don't just magically happen. Each of the steps requires an enzyme to make it happen and those enzymes have cofactors that are required in order for them to work. In addition, nutrients don't just automatically cross into the mitochondria; some are shuttled in with carriers.
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Compounds they require to function properly:

1. CoQ10
2. B Vitamins
3. L-Carnitine
4. D-ribose
5. Iron
6. Alpha lipoic acid (6)
7. Thyroid hormone (T3 and T2)

CoQ10 is a fat soluble substance; hence its position within the inner cell membrane of the mitochondria.  It has three reduced states:

1. Ubiquinone - fully oxidized, missing both electrons it's capable of carrying
2. Semiquinone - missing one electron
3. Ubiquinol - fully reduced, carrying both electrons it can can carry

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Ubiquinone is typically used as a supplement when mitochondria support is the goal. Ubiquininol can be used as an antioxidant because it carries two electrons that can be used to limit the damage caused by reactive oxygen species (ROS). ROS create damage because they have an unpaired electron that is seeking to be matched with another electron. This extra electron can be gained from lipids within the body or from DNA, which damages these structures. Ultimately antioxidants are electron donors and ubiquinol is one of many electron donors that serve as antioxidants. The role of CoQ10 within the mitochondria is as an elecron carrier, so ubiquinone is best. CoQ10 has been shown to lower levels of oxidized purines, which are the damaged pieces of DNA that occur as a result of oxidative stress, in cells of those with Down syndrome (7).

B vitamins are needed as enzyme cofactors for each step of the TCA and within the electron transport chain (image 4). These B vitamins can quickly become depleted in a diet that contains processed grains because those grains provide glucose but are stripped of the bran and germ that contain B vitamins to help our bodies get energy from the glucose. Deficiencies in B vitamins are also very common in those who have an imbalance in their gut flora like small intestinal bacterial overgrowth (SIBO) or candida overgrowth (8).

Carnitine has one role in the body and that is to shuttle fatty acids into the mitochondria so that they can be used for energy. That's it. It does nothing else. Carnitine is synthesized in the body from lysine and methionine. It's also obtained through eating meat, especially red meat, hence it's name (carne = meat). In 2005 researchers tested carnitine's impact on mitochondria function in aging rats. They found that it improved the function of the TCA and the flow of electrons through the electron transport chain (9).  In addition, children with Down syndrome have been shown to have lower carnitine levels than typical children (10). Because mitochondrial function has been linked to cognition (11) it follows that carnitine supplementation can help dementia and cognitive impairment that is linked to mitochondrial dysfunction.  In fact, researchers in the UK found that acetyl l-carnitine did improve cognition in those with mild cognitive impairment and mild Alzheimer's disease (12). Acetyl l-carnitine is the form of carnitine that crosses the blood brain barrier, so it's preferred when support of cognition is the goal.

Lastly, carnitine deficiency has been shown to cause delayed gut motility leading to vomitting after meals, oral drooling, delayed gastric emptying and constipation (13). This makes sense given how much muscle function is impacted by mitochondria function and optimal gut motility is a consequence of healthy muscle function.

Iron deficiency is the most common nutrient deficiency worldwide. One of the main symptoms of iron deficiency is fatigue. This is, in part, due to iron's role as a cofactor in several enzymes found within the TCA as well as the electron transport chain.

Alpha lipoic acid (ALA) is a fatty acid that is synthesized within mitochondria and acts as a very potent antioxidant. It can also be obtained in the diet in the form of lipoyllysine and is highest in animal tissue (kidney, heart, liver) and green plants like spinach and broccoli (18). In addition to being an antioxidant ALA is also required as a cofactor for one of the enzyme complexes that makes up pyruvate dehydrogenase. This enzyme complex converts pyruvate (made from glucose) to acetyl-CoA that is the entrance point for the TCA. It's thought that ALA deficiency doesn't exist as the body typically makes what it needs. However, supplementing with ALA has been shown to support brain health, cardiovascular health, heavy metal chelation, insulin function and inflammation (19, 20). It's repeatedly been shown to work well when supplemented together with acetyl l-carnitine (21,22, 23, 24).

Thyroid hormone is often overlooked for it's vital role in mitchondrial function.  There are several forms of thyroid hormone, thyroxine (T4), triiodothyronine (T3), 3,5 diiodo-l-thyronine (T2) and monoiodothyronine (T1). Each of these forms are named based on the number of iodine atoms attached to them.  The two forms that play an important role in mitochondria function are T3 and T2. T3 is often called "active" thyroid hormone because it's necessary for the function of every cell within the body. T3 acts as a transcription factor within the cell, literally turning on certain genes within the nucleus of each cell that contribute to the function of that cell. T3 and T2 hormone work in a similar manner within the mitochondria; they turn on mitochondrial genes that code for key proteins with the electron transport chain (image 6).  

The good news is that mitochondrial function can be assessed through blood and urine tests as well as symptoms.  These tests include:

• Plasma free carnitine and acylcarnitine
• Urine organic acid test (TCA cycle intermediates, lactic acid, pyruvic acid, ketone and fatty acid oxidation, 3-methylglutaric, 3-hydroxyglutaric, 3-methylglutaconic)
• Plasma amino acids, alanine:lysine ratio or elevated alanine (27)

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Not all doctors will order these tests, nor will they know how to interpret them. It's important to work with a doctor who has training or is educated to understand these tests. Interpreting these labs is both simple yet complicated. For example, if carnitine levels are low supplementation is warranted. Other markers that indicate a need for carnitine are urinary fatty acids, adipic and suberic acid. When they are elevated in the urine it indicates that they are not being shuttled into mitochondria and not being used, hence the need for carnitine. Doses recommended are in the range of 20-100 mg/kg/day for children (28). Elevated urinary pyruvic acid can indicate a need for alpha lipoic acid as well as B1, B2 and B3. Elevated intermediates of the TCA in the urine can indicate a need for cofactors of the enzyme needed to convert that intermediate to the next step of the TCA, typically these are B vitamins. This information is greatly simplified and assessment of what each patient needs to support their individual mitochondrial needs requires an evaluation from a trained physician.

I reported on the outcome of helping a 14 month old boy with Down syndrome in my blog post Customized Treatment for Children with Down Syndrome. His initial organic acid test results indicated significant mitochondrial dysfunction with several elevations in his TCA intermediates as well as very high adipic and suberic acid levels, indicating a need for carnitine. He was only supplemented with carnitine and treated for gastrointestinal dysbiosis, which was the greatest contributing factor to his B vitamin deficiencies. His repeat organic acid results as well as his improved development and cognition indicated that mitochondria function had improved. 

Many children with special needs (Down syndrome, autism, and others) would benefit from screening for mitochondrial dysfunction. The long term impact to health and cognition if mitochondrial dysfunction goes unaddressed are profound. The benefits of supporting mitochondrial function are far-reaching for the patient given the many organ systems that are impacted by cellular energy production.

Mitocondrial dysfuntion is currently not recognized by conventional medical physicians who often choose to prescribe pharmaceuticals for symptoms in lieu of addressing the root cause of disease. Fortunately physicians who are trained in mitochdondrial function exist and include Functional Medicine practitioners, Naturopathic physicians, Biomedical doctors and MAPS doctors.

One thing many researchers fail to acknowledge when studying Down syndrome is that they may actually be seeing the effects of hypothyroidism and not the over-expression of chromosome 21.  Hypothyroidism is more common in children with T21 than is reported.  Most doctors only check TSH (thyroid stimulating hormone) and free T4 (thyroxine).  The process of thyroid hormone within the body is much more complicated than that and only testing these two lab values misses a lot of hypothyroidism.  In addition, many doctors accept a TSH higher than 3, 4 and even 6 or 7 mIU/L to be normal for individuals with Down syndrome. An optimal TSH is closest to 1.5 mIU/L (1) and ideally it should be below 2.5 mIU/L.  The most detrimental aspect of hypothyroidism being missed in individuals with Down syndrome is the dismissive attitudes of many doctors accepting the obvious symptoms of hypothyroidism (2) as typical for Down syndrome.  For a more indepth explanation of this I recommend reading Thyroid and the Developing Brain.

The role that active thyroid hormone (triiodothyronine) plays in myelin formation, oligodendrocyte differentiation and function is strong.  A study from 1997 stated, "Our results indicate that thyroid hormones participate in the control of the progenitor cell proliferation and differentiation as well as in oligodendrocyte maturation and that these two T3-regulated events are independent." (3)  An even older study from 1985 also emphasized a direct effect of T3 on myelination. (4)  The impact of thyroid hormone on myelination has been known for a long time.  Yet, funding for research, as is often the case, is focused on finding new drugs to help those who are impacted by demyelinating disease like Multiple Sclerosis or Down syndrome.

Fortunately, more recent published information exists supporting the importance of thyroid hormone on the developing brain.  A current, very comprehensive overview of this was written by Juan Bernal, M.D, Ph. D. and is called Thyroid Hormones in Development and Function.  Image 4 below comes from the new study published in Neuron revealing the decrease in neuron connections in individuals with Down syndrome.  The same lack of neuron connections in hypothyroidism can be seen in Image 5 from Dr. Bernal's review.  

Michelle Diament suggests the potential use of myelin-regenerating drugs for those with Down syndrome as a means to counter the imapct that demyelination can have in her article for Disability Scoop (5). I recommend uncovering the root cause of demyelination, dysfuntional oligodendrocyte differentiation and decreased neuron connection before using pharmaceuticals that can potentially have significant side effects, including:

• Fatigue
• Flu-like symptoms
• Depression and mood changes
• Gastrointestinal problems (6)

The key to optimizing myelination and early brain development is optimizing this process in utero.  More research is needed to understand the role that thyroid hormone plays in early brain development in infants with Down syndrome and how to optimize it.  Optimizing thyroid hormone in adults is potentialy as important as optimizing it in early development.  Remaud, et al wrote Thyroid Hormone Signaling and Adult Neurogenesis in Mammals. They give a vast amount of evidence supporting the importance of optimal thyroid hormone function in all stages of life.  As well, myelination has been reported to continue well into adolescence. (7)
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There's support for other means of optimizing myelination than just ensuring proper thyroid hormone function.  B12 and folate are critical for early brain development and myelination formation in utero. (8)  Most importantly, however, is iron.  Todrich, et all have stated, "The importance of iron in myelin production has been demonstrated by studies showing that decreased availability of iron in the diet is associated with hypomyelination. " (9)  Radlowski and Johnson stated, "...the need and usage of iron by oligodendrocytes does not end during the perinatal period and that the adult brain still requires adequate iron." (10) Iron levels are commonly low in children with Down sydrome. (11, 12) ​

Choline is another key nutrient needed for myelination and has been shown to be effective for remyelination. (13) ​Barbara Strupp's important work reveals that prenatal choline supplementation "markedly improved spatial cognition" in Ts65Dn mice. (14) One published report of a 2.5 year old boy with Down syndrome revealed "definitive" improvement in his speech and language skills in addition to his gross motor skills after supplementation with phosphatidylcholine. (15) The important role that phosphatidylcholine plays in myelin formation is most likely a mechanism that supported cogniton in these two examples.

I suggest that any research that intends to study the impact that the over-expression of chromosome 21 has on any areas of brain function including myelination remove the variables that hypothyroidism and nutrient deficiencies can have on these processes. If your child or loved one is taking any or all of these nutrients and has had early treatment for hypothyroidism it's possible that this new information about hypomyelination does not apply to them.  The use of pharmaceuticals to treat myelination issues in children with Down syndrome should be approached cautiously given the many other ways that myelination can be supported.