"CFS symptoms resemble a hypothyroid state" but...

I am a little late getting to the paper published by Begoña Ruiz-Núñez and colleagues [1] observing that, at least for some diagnosed with chronic fatigue syndrome (CFS), clinical findings related to thyroid function might "resemble a mild form of “non-thyroidal illness syndrome” and “low T3 syndrome” experienced by a subgroup of hypothyroid patients receiving T4 monotherapy." But I did get here eventually. Before heading into this paper, I'm gonna link to one of the 'already prepared' discussions on the Ruiz-Núñez findings (see here). My analysis is pretty similar but not entirely the same...

So: "We studied 98 CFS patients (21–69 years, 21 males) and 99 age- and sex-matched controls (19–65 years, 23 males)" was the starting point, as participants provided blood samples and 24-hour urine samples onward to various analyses being carried out. This included: "the measurement of routine hematological parameters [Hb, hematocrit, WBC, red blood cells (RBC), and thrombocytes]" and more specifically: "parameters of thyroid function, low-grade inflammation and gut wall integrity..., together with secondary markers of inflammation." Those 'parameters of thyroid function' included various measures of free and total levels of T3 and T4 required to ascertain the presence of "low-T3 syndrome." I was impressed to see that a measure of gut wall integrity was also on the research menu in the form of plasma zonulin levels being included (albeit analysed via ELISA and bearing in mind the issues that have emerged with that particular method).

Results: "Chronic fatigue syndrome patients exhibited lower FT3, TT4, TT3, %TT3, SPINA-GD, and SPINA-GT, lower ratios of TT3/TT4, FT3/FT4, TT3/FT3, and TT4/FT4; and higher %rT3 and rT3/TT3 ratio." These findings were based on 'group' comparisons with those sex-matched not-CFS controls, and point to some 'issues' with thyroid function in general. Coupled to other thyroid related findings, the Ruiz-Núñez suggest that lower levels of thyroid hormones were detected but "distinct from thyroidal disease" typical levels of thyroid-stimulating hormone (TSH) were also reported. TSH is the stuff that tells the thyroid gland to make thyroid hormone (thyroxine (T4)), where T4 is, in effect, the starting material for T3 (triiodothyronine). Where there are suitable levels of TSH but lower levels of T4 and/or T3, one gets the impression that it's more about what's 'happening' to T3 and T4 over and above issues with their production. Indeed, the collected findings led authors to talk about that 'low T3 [triiodothyronine]syndrome' as being potentially pertinent to their findings in relation to CFS. Going back to those plasma zonulin findings, and there is just a sentence from Ruiz-Núñez and colleagues: "Zonulin, a parameter of intestinal permeability... was lower in CFS patients as compared to controls" but not much else.

I'm not particularly au fait with all the details of low T3 syndrome in the context of CFS or anything else so can't really add too much more. From what I gather, this is not a CFS-exclusive condition but does seemingly tap into talk about CFS being reflective of a "hypometabolic state" (see here). Questions about how to 'treat' such thyroid-related issues in the context of CFS remain unanswered, despite authors talking about "trials with, e.g., T3 and iodide supplements" being potentially indicated. I say this bearing in mind that the focus on biochemistry in the Ruiz-Núñez paper could perhaps, have been complemented by a little more on the presentation of clinical symptoms too.

In short, quite a bit more investigation in this area is indicated...

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[1] Ruiz-Núñez B. et al. Higher Prevalence of “Low T3 Syndrome” in Patients With Chronic Fatigue Syndrome: A Case–Control Study. Front. Endocrinol. 2018. Mar 20.

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MoBa does... maternal pregnancy iodine intake and offspring ADHD symptoms and diagnosis

Yet another 'MoBa does...' post today, reflecting data derived from the Norwegian Mother and Child Cohort Study and the findings reported by Marianne Hope Abel and colleagues [1] (open-access available here).

Maternal pregnancy iodine intake (both calculated from food sources and also as a supplement) was the starting variable, where responses to "a food frequency questionnaire (FFQ)" provided researchers with enough data to categorise mums-to-be in terms of their iodine intake. Iodine, by the way, is something of an important nutrient from many biological reasons; not least for optimal thyroid function. During pregnancy, suitable iodine levels are also seemingly required to ensure that the developing child is able to reach their full potential (see here).. seemingly.

Alongside, researchers also looked at both children diagnosed with attention-deficit hyperactivity disorder (ADHD) and "maternal report of child ADHD symptoms at eight years of age" on the basis of other data talking about "a negative impact on child behavior problems when mothers had inadequate iodine intake from food and initiated use of supplemental iodine in the first trimester of pregnancy." Keep in mind that last part about supplemental use during early pregnancy...

So, including some 77,000 mother-child pairs where "for 27,945 there were data on maternally reported ADHD scores when the child was aged eight years", what did the researchers find?

"Iodine from food was significantly associated with maternally reported child ADHD symptoms at eight years of age... but not with risk of child ADHD diagnosis." Authors expanded on this observing that the 'inattention' side of ADHD symptoms, derived from a questionnaire covered in independent research [2], was the driving force behind the connection being made, not the hyperactivity subscale. They also noted that "maternal iodine intake of less than ~200 µg/day" seemed to be the crucial cut-off point when it came to those maternal reports of ADHD symptoms.

But... I'm sure it can't have escaped your attention that although maternal reports of offspring ADHD symptoms - indeed, inattention - *correlated* with maternal iodine intake, there was little to see when it came to "risk of specialist-diagnosed ADHD in the child." Indeed, the authors also note that they found "no evidence of any beneficial effect of supplemental iodine in pregnancy" and even that "initiating iodine supplement use within the first trimester in mothers with inadequate iodine intake from food (<EAR) was associated with both an increased risk of ADHD diagnosis and higher ADHD symptom score at eight years of age."

Science is [almost] never clear-cut in the conclusions it arrives at and the Abel results just add to that sentiment. Given that this authorship group seemingly having a considerable research interest in all-things iodine and health, I'm assuming that these latest results were quite the talking point. Certainly, just a little bit different from their other recent publication on this topic [3] that concluded: "Maternal iodine intake below the Estimated Average Requirement during pregnancy was associated with symptoms of child language delay, behavior problems, and reduced fine motor skills at 3 y of age" but perhaps not with the supplementation angle in mind: "results showed no evidence of a protective effect of iodine supplementation during pregnancy."

I don't know what and how much to make of the findings as they stand, aside from suggesting that other recent findings [4] also questioning the value of daily iodine supplementation "in mildly iodine-deficient pregnant women" perhaps add to the discussions in this area. MoBA represents a great resource in these days of population science, so one can't blame the findings on a lack of "large sample size, prospective design, extensive collection of data, and the possibility of linking the cohort to national registries." It could, therefore, well be that talk on iodine supplementation during early pregnancy perhaps needs a lot more science behind it before anyone makes any grand, sweeping claims about its usefulness...

To close, in case you're wondering about the photo included in this post, it's all part of the Public Health England 'celebrations' for 100 years of public health marketing (see here).

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[1] Abel MH. et al. Maternal Iodine Intake and Offspring Attention-Deficit/Hyperactivity Disorder: Results from a Large Prospective Cohort Study. Nutrients. 2017 Nov 13;9(11). pii: E1239.

[2] Silva RR. et al. A rating scale for disruptive behavior disorders, based on the DSM-IV item pool. Psychiatr Q. 2005 Winter;76(4):327-39.

[3] Abel MH. et al. Suboptimal Maternal Iodine Intake Is Associated with Impaired Child Neurodevelopment at 3 Years of Age in the Norwegian Mother and Child Cohort Study. J Nutr. 2017 Jul;147(7):1314-1324.

[4] Gowachirapant S. et al. Effect of iodine supplementation in pregnant women on child neurodevelopment: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017 Nov;5(11):853-863.

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Iodine and autism (again)

Welcome back to Questioning Answers in 2016.

Let's continue our travels down the autism peer-reviewed research path by starting with some brief discussion of the findings reported by Anna Błażewicz and colleagues [1] talking about iodine and autism.

With the aim of assessing "the iodine status of Polish boys with severe autism compared to their healthy peers" (authors words not mine), researchers reported results for various iodine and related measures (including metabolites related to thyroid function). They concluded that: "Thyroid hormones were within normal reference ranges in both groups while urinary iodine was significantly lower in autistic boys suggesting that further studies into the nonhormonal role of iodine in autism are required."

I've previously covered the topic of iodine and autism on this blog (see here). That time as this, we are talking about quite a few participants with autism presenting with iodine deficiency keeping in mind that the measurement of iodine in urine is actually quite a good way of ascertaining nutritional iodine status [2]. Błażewicz et al also suggested that various presented symptoms pertinent to autism might 'correlate' with iodine status; something again suggested in previous, independent results [3].

Insofar as the 'nonhormonal' uses of iodine and what deficiency in [some] autism might mean, I'd be minded to point other areas of interest outside of just cognitive effects [4]. The intersection between iodine, selenium and iron is worthwhile mentioning in light of the various co-dependencies of these nutrients in maintaining health and wellbeing. Other research has noted deficiencies in these three nutrients as part of a pattern in some autism [5]. Together with a suite of peer-reviewed literature suggesting that there maybe much more to see when it comes to micronutrient levels in at least some cases of autism, the onus once again is on screening followed by evidence-guided decisions on possible intervention(s).

Music, and as always at this time of year, think Vienna and An der schönen blauen Donau...

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[1] Błażewicz A. et al. Iodine in autism spectrum disorders. Journal of Trace Elements in Medicine and Biology. 2015. Dec 4.

[2] Delange F. et al. Determining median urinary iodine concentration that indicates adequate iodine intake at population level. Bulletin of the World Health Organization. 2002; 80: 633-636.

[3] Hamza RT. et al. Iodine Deficiency in Egyptian Autistic Children and Their Mothers: Relation to Disease Severity. Arch Med Res. 2013 Oct 9. pii: S0188-4409(13)00222-1.

[4] Redman K. et al. Iodine Deficiency and the Brain: Effects and Mechanisms. Crit Rev Food Sci Nutr. 2015 Apr 16:0.

[5] Blaurock-Busch E. et al. Toxic Metals and Essential Elements in Hair and Severity of Symptoms among Children with Autism. Maedica (Buchar). 2012 Jan;7(1):38-48.

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Błażewicz, A., Makarewicz, A., Korona-Glowniak, I., Dolliver, W., & Kocjan, R. (2015). Iodine in autism spectrum disorders Journal of Trace Elements in Medicine and Biology DOI: 10.1016/j.jtemb.2015.12.002

Parental autoimmunity and offspring autism risk... yet again

Here we go again.

"A positive association between maternal autoimmune diseases and the risk of ASD [autism spectrum disorder] in offspring was identified assuming a fixed effect model." Further: "Maternal autoimmune disease is likely to be an independent risk factor of ASD in offspring."

Those were the findings and conclusions published by Shao-wei Chen and colleagues [1] as part of their systematic review and meta-analysis of the available peer-reviewed literature looking at how maternal autoimmune disease might influence offspring risk of autism. Researchers specifically observed "statistically significant associations between maternal autoimmune diseases developed during pregnancy or maternal thyroid disease and the risk of ASD in offspring."

This is not new news. Not so long ago I discussed another meta-analysis that concluded that there was an overall increased risk of autism in children with a family history of autoimmune disease (see here) including a focus on specific autoimmune conditions (see here). The idea that thyroid issues might be linked to offspring autism has also been covered on this blog (see here) and not just with core autism as a possible feature (see here). Such a relationship might, I assume, be complicated by issues with iodine availability too (see here).

The implications of the Chen findings? Well, the calls for quite a bit more research on how autoimmune disease might be 'linked' to some autism grow a little louder. The possibility of preferential screening of offspring where certain autoimmune diseases might be a feature in mums and/or dads also garners a little more support.

Music: Foster The People - Pumped up Kicks.

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[1] Chen SW. et al. Maternal autoimmune diseases and the risk of autism spectrum disorders in offspring: a systematic review and meta-analysis. Behav Brain Res. 2015 Aug 29. pii: S0166-4328(15)30170-4.

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Chen SW, Zhong XS, Jiang LN, Zheng XY, Xiong YQ, Ma SJ, Qiu M, Huo ST, Ge J, & Chen Q (2015). Maternal autoimmune diseases and the risk of autism spectrum disorders in offspring: a systematic review and meta-analysis. Behavioural brain research PMID: 26327239

AAP policy statement on iodine deficiency and pollutants

The quite recent policy statement from the American Academy of Pediatrics (AAP) drafted by Rogan and colleagues [1] is the source for today's short(ish) post. Highlighting a growing concern on the issue of iodine deficiency in women of reproductive age, the policy document also raises awareness of "commonly encountered environmental chemicals" potentially exacerbating such deficiency, and in particular "thiocyanate, nitrate and perchlorate". These chemicals are specifically mentioned because of their competition "for transport by the sodium iodide symporter (NIS)" involved in thyroid hormone biosynthesis. The paper by De Groef and colleagues [2] (open-access here) provides quite a good overview of the hows and whys of this chemical inhibition.

With my autism research hat on and hopefully without trying to make mountains out of molehills, I was interested in this latest policy statement in light of some interesting work talked about on this blog before. The Stine Andersen paper [3] covered in a previous post (see here) kinda sums up where we seem to be with regards to the 'association' between maternal hypothyroidism and subsequent heightened offspring risk of autism or an autism spectrum disorder (ASD). I did, on that post, also talk about iodine and the importance of iodine when it comes to making thyroid hormones. That iodine deficiency has also itself been linked to risk of offspring autism (see here) is another potentially important point to make.

The slightly more contentious area of 'chemical' (yes, that word again) involvement affecting iodine transport also seems to overlap with at least some work/speculation in the autism research arena. The paper by Gustavo Román [4] talking about environmental antithyroid agents and "transient in utero hypothyroxinemia" with autism in mind might be relevant. Román has already done some work in the area of thyroid hormones and offspring autism risk (see here) based on analyses from the Generation R cohort [5] (open-access). In that review article [4] there is talk about thiocyanate for example, and it being found in both food and other environmental sources as well as quite a few more other agents which have the ability to interfere with thyroid manufacture or function.

Perchlorate and autism is a slightly less well researched area. The paper by Chang and colleagues [6] is a good first effort when it came to assessing whether perchlorate-contaminated water might have any population-wide connection to rates of autism based on an ecological study design. On that occasion, no link was reported. That being said, measuring autism rates from a social healthcare program and perchlorate levels in drinking water from local water authority data might not necessarily provide the most accurate data as per the implications from the data from Mandell and colleagues [7] for example and the question of individual exposure patterns (something which might also be relevant to the recent pesticide-autism work too).

Given what is already known about maternal iodine deficiency and offspring outcome [8] the AAP policy document should be a welcome addition to the recommendations to US healthcare professionals in terms of ensuring iodine sufficiency particularly during pregnancy and early nursing periods. The addition of environmental variables also potentially affecting iodine levels whilst not shared by everyone [9] is something which requires further investigation. The more specific discussion about thiocyanate exposure from tobacco smoke in particular, taps into more generalised guidance for women to avoid smoking and second-hand smoke during pregnancy.

Music to close, and a bit of a favourite of mine... Fireflies (best listened to loud).

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[1] Iodine Deficiency, Pollutant Chemicals, and the Thyroid: New Information on an Old Problem. Council on Environmental Health. Pediatrics. 2014. 26 May.

[2] De Groef B. et al. Perchlorate versus other environmental sodium/iodide symporter inhibitors: potential thyroid-related health effects. Eur J Endocrinol. 2006 Jul;155(1):17-25.

[3] Andersen S. et al. Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study. BJOG. 2014 Mar 10.

[4] Román GC. Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents. J Neurol Sci. 2007 Nov 15;262(1-2):15-26.

[5] Román GC. et al. Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol. 2013 Nov;74(5):733-42.

[6] Chang S. et al. Pediatric neurobehavioral diseases in Nevada counties with respect to perchlorate in drinking water: an ecological inquiry. Birth Defects Res A Clin Mol Teratol. 2003 Oct;67(10):886-92.

[7] Mandell DS. et al. Age of diagnosis among Medicaid-enrolled children with autism, 2001-2004. Psychiatr Serv. 2010 Aug;61(8):822-9.

[8] Zimmerman MB. The effects of iodine deficiency in pregnancy and infancy. Paediatr Perinat Epidemiol. 2012 Jul;26 Suppl 1:108-17.

[9] Leung AM. et al. Environmental perchlorate and thiocyanate exposures and infant serum thyroid function. Thyroid. 2012 Sep;22(9):938-43.

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(2014). Iodine Deficiency, Pollutant Chemicals, and the Thyroid: New Information on an Old Problem PEDIATRICS, 133 (6), 1163-1166 DOI: 10.1542/peds.2014-0900

Blocking FRAAs and thyroid function in autism

FRAAs - folate receptor alpha autoantibodies - may correlate with reduced thyroid function in cases of autism is the primary finding from the paper by Richard Frye and colleagues [1] (open-access). And immediately my attention is piqued at the possibility of a link...

FRAAs have been mentioned before on this blog (see here) based on a really interesting paper by the autism research tag team that is Frye and Rossignol [2] who continue to give when it comes to peer-reviewed research on autism. On that occasion, they reported: "serum FRA [folate receptor α autoantibodies] concentrations were measured in 93 children with ASD [autism spectrum disorder] and a high prevalence (75.3%) of FRAs was found". The net result was that there may be issues with the availability of folate, and as in the condition cerebral folate deficiency (CFD), there may be some use in looking at folinic acid (leucovorin) to normalise levels of 5-methyltetrahydrofolate. But please note I'm advocating nothing on this blog just describing findings.

In their most recent paper, Dr Frye and colleagues took things one stage further:

• Levels of blocking and binding FRAAs were measured from serum samples donated by 32 children diagnosed with an autism spectrum disorder (ASD). Based on participants' medical records, levels of thyroid stimulating hormone (TSH) were "abstracted" and correlated with FRAAs measures.
• Results: bearing in mind this was a 'let's see' study with no control groups and TSH values derived from medical records, the authors reported: "No significant relationship was found between the binding FRAA and TSH. However, a higher blocking FRAA titer was significantly related to a higher TSH concentration". The correlation (r) came out at 0.36, which is OK but not necessarily what one might call a strong relationship.
• They add: "Patients who were positive for the blocking FRAA were found to have a significantly higher TSH concentration as compared to patients who were negative for the blocking FRAA". 

There are a few other points to comment on in this paper. First is the focus on thyroid function and autism. I've talked a few times about maternal thyroid levels and how they may correlate to some extent with autism risk (see here and see here). The research literature on thyroid levels in people with autism is slightly more scant (see here), and bearing in mind that there are various other thyroid measures that might be relevant, the focus on TSH alone rather limits the conclusions one can draw about thyroid function in this study. Indeed, none of the participants in this sample had "an abnormally low TSH" result and only a few had "abnormally elevated TSH".

Allied to thyroid function, and mentioned by Frye et al is the issue of iodine deficiency, which again, has been mentioned on this blog with autism in mind (see here). Iodine plays an important role in the production of thyroid hormones. Unfortunately the current study did not assay for iodine levels so we are to some extent left in the dark about any role.

There's little more for me to say about this trial outside of the need for studies looking at rather more direct measures, and a few more of them particularly pertinent to the functions of the thyroid in an autism group. I might also add that in view of the suggestion that a milk-free diet "downregulates folate receptor autoimmunity" as per the work by Ramaekers and colleagues [3] (open-access) looking at CFD, future research might also assess any effect this might have on any thyroid link too. Got milk (opioid peptides)?

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[1] Frye RE. et al. Folate receptor alpha autoantibodies modulate thyroid function in autism spectrum disorder. NAJMS 2014; 7: 53-56.

[2] Frye RE. et al. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013; 18: 369-381.

[3] Ramaekers VT. et al. A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Dev Med Child Neurol. May 2008; 50(5): 346–352.

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Richard E. Frye, Jeffrey M Sequeira, Edward Quadros, & Daniel A. Rossignol (2014). Folate receptor alpha autoantibodies modulate thyroid function in autism spectrum disorder N A J Med Sci. , 7 (2), 53-56 : 10.7156/najms.2014.0702053

Maternal thyroid dysfunction and autism or ADHD?

The paper by Andersen and colleagues [1] talking about the risk of offspring attention deficit hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD) where mothers presented with "maternal thyroid disease" is the source material for this post.

The Circus @ Wikipedia 

Based on data derived from Denmark, and those very useful Danish health registries which seem to be producing all-manner of potentially important information (see here), researchers reported that: "Maternal hyperthyroidism diagnosed and treated for the first time after the birth of the child increased the risk of ADHD in the child (adjusted HR 1.23; 95% CI 1.05-1.44), whereas hypothyroidism increased the risk of ASD (adjusted HR 1.34; 95% CI 1.14-1.59)".

Upon reading the suggested correlation between maternal hypothyroidism - where thyroid function is reduced - and something of an increased risk for an autism diagnosis in offspring, my mind headed back to the study by Gustavo Román and colleagues [2] talked about in this post, and their findings of "a consistent association between severe, early gestation maternal hypothyroxinemia and autistic symptoms in offspring". Of course, there are some differences between the way the Anderson and Román studies were conducted (registry diagnosis of thyroid dysfunction post-pregnancy vs. laboratory testing of thyroid function during early pregnancy) but the similar direction of the findings with autism in mind is interesting.

Equally interesting was the suggestion that maternal hyperthyroidism - an overactive thyroid - was related to some heightened risk of offspring ADHD in the Anderson cohort. A quick trawl of the limited research carried out in this area reveals some support for this assertion as per the data produced by Päkkilä and colleagues [3] who reported: "Increases in maternal TSH [thyroid stimulating hormone] in early pregnancy showed weak but significant association with girls' ADHD symptoms". That being said, I don't doubt that this is going to be a complicated relationship as per other reports on things like maternal thyroid autoimmunity during pregnancy and offspring outcomes [4] and the issue of iodine and offspring outcome [5] which has previously been talked about on this blog with autism in mind (see here). The fact that autism and ADHD can and do present comorbid in quite a few people adds to the complication.

I'd be hard-pressed to offer anything definitive about how and why thyroid function might impact specifically on the risk of diagnoses such as ADHD and autism outside of what is already known about maternal thyroid function and infants (see here). I assume as part of a larger clinical picture, there may be some direct effects specifically acting on the infant during the nine months that made us as well as other peripheral effects acting on for example, delivery issues as per the correlation between thyroid function and something like preterm birth risk [6] which might play some role [7].

Similarly when talking about the 'hows' of how issues with thyroid function come about in mums-to-be, one is faced with an array of possible factors. I could start going on about some of the genetics of thyroid disease [8] but I have neither the time, space or expertise to provide any thorough overview. Environment can also play a role as per the factors listed on this website so take your pick as to what might be relevant or not to cases. With the continuing interest in environmental effects and conditions like autism and ADHD, I might direct you to some of the work done on endocrine disruptors and thyroid functions [9] but with the realisation that the picture is going to be a complicated one varying from one group to the next, even one person to the next.

Still, the Anderson results further add to the interest looking at maternal thyroid function and offspring outcome and merit some further investigations in this area. Indeed, thyroid function is turning up in all manner of places these days [10] and perhaps point to some interesting associations which might have some important knock-on effects [11] ...

So, New Kids On The Block making a come-back.... You Got It!

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[1] Andersen S. et al. Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study. BJOG. 2014 Mar 10.

[2] Román GC. et al. Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol. 2013 Nov;74(5):733-42.

[3] Päkkilä F. et al. The impact of gestational thyroid hormone concentrations on ADHD symptoms of the child. J Clin Endocrinol Metab. 2014 Jan;99(1):E1-8.

[4] Ghassabian A. et al. Maternal thyroid autoimmunity during pregnancy and the risk of attention deficit/hyperactivity problems in children: the Generation R Study. Thyroid. 2012 Feb;22(2):178-86.

[5] Vermiglio F. et al. Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries. J Clin Endocrinol Metab. 2004 Dec;89(12):6054-60.

[6] Stagnaro-Green A. et al. The thyroid and pregnancy: a novel risk factor for very preterm delivery. Thyroid. 2005 Apr;15(4):351-7.

[7] Silva D. et al. Environmental risk factors by gender associated with attention-deficit/hyperactivity disorder. Pediatrics. 2014 Jan;133(1):e14-22.

[8] Medici M. et al. Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease. PLoS Genet. 2014 Feb 27;10(2):e1004123.

[9] Hofmann PJ. et al. Interference of endocrine disrupters with thyroid hormone receptor-dependent transactivation. Toxicol Sci. 2009 Jul;110(1):125-37.

[10] Wysokiński A. & Kłoszewska I. Level of Thyroid-Stimulating Hormone (TSH) in Patients with Acute Schizophrenia, Unipolar Depression or Bipolar Disorder. Neurochem Res. 2014 Apr 11.

[11] van der Pals M. et al. Prevalence of thyroid autoimmunity in children with celiac disease compared to healthy 12-year olds. Autoimmune Dis. 2014;2014:417356.

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Andersen S, Laurberg P, Wu C, & Olsen J (2014). Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study. BJOG : an international journal of obstetrics and gynaecology PMID: 24605987

Iodine deficiency and autism

With all the recent-ish chatter about dietary quality for those on the spectrum (see here), coupled with a hint of something like the mechanisms of malabsorption being linked to specific cases (see here), the potential issue of 'nutritional deficiency' in relation to autism represents a pretty constant research topic these days.

 Iodine @ Wikipedia

I've talked before about research defining a deficiency in certain vitamins and minerals in relation to cases of autism on this blog; be it in relation to the vitamin-of-the-hour, vitamin D (see here) or vitamin B12 (see here) or something like zinc (see here).

The picture is a complicated one and not necessarily a universal one in terms of prevalence across the autism spectrum nor being solely due to poor eating patterns. But given the increasing understanding of the importance of nutrition to mental and physical health and wellbeing, one would expect quite a lot more to be said on this topic over the coming years.

The paper by Rasha Hamza and colleagues* detailing findings in relation to iodine in cases of autism and other family members adds to the interest. Based on a relatively small participant group, the authors reported that: "Of autistic children and their mothers, 54% and 58%, respectively, were iodine deficient". This contrasted with none of the 50 control group children or mothers presenting with iodine deficiency (ID).

Before progressing through the Hamza study further, I might point out that the British Dietetic Association (BDA) carries quite a detailed information sheet about iodine (see here) as does the US Office of Dietary Supplements (see here). Iodine is sourced mainly from food, and as you'll see from the links, outside of seafood and shellfish, milk and dairy products are one of the biggest dietary sources of iodine. Casein-free diet anyone?

A primary use for iodine in the body is for the production of thyroid hormones. Without going over previous ground, there is some research history when it comes to thyroid hormone and autism as per discussions on the measurement of thyroid hormone levels in autism (see here) and more recent research talking about maternal thyroid levels and offspring 'autistic symptoms' (see here). Dare I even mention the possible environmental variables which have been associated with thyroid function too?

Back to the Hamza paper. As well as measuring levels of urinary iodine (UI) - which apparently is quite a good way of measuring iodine intake** - the researchers also scored child participants with autism using the CARS so as to have some measure of the extent of their presented symptoms. That and examining levels of some of the various thyroid hormones, they were able to arrive at a few other preliminary, but potentially important conclusions.

"Childhood Autism Rating Scale (CARS) score correlated negatively with UI (r = -0.94, p <0.001)". I'm no statistician (add it to the long list of things for which I'm more amateur than professional) but a correlation (r) of -0.94 seems pretty good to me bearing in mind that (1) or (-1) indicates a perfect positive and negative correlation respectively. This data translates as a higher CARS score being generally associated with lower levels of urinary iodine. Further, when looking maternal and child UI output and other thyroid hormones, the authors reported some interesting positive correlations between child and mother values obtained.

It would be easy to say that the Hamza study has some methodological issues. Outside of the quite small participant group, and their exclusive focus on Egyptian families, this was very much a snapshot study in terms of looking at participants at a particular point in time. CARS, like many other autism screening and assessment instruments, is still quite a subjective measure also and who's to say that if this study was repeated a week or a month later, whether similar results would be had with the same group. And then there is that milk-free dietary issue to also consider...

But with all that in mind, this remains an interesting study. I note that other independent groups have also reported issues with iodine being related to cases of autism as per the findings by Blaurock-Busch and colleagues*** (open-access here) and a familiar name to this blog (see here) Jim Adams and his paper***. I was also drawn to an interesting communication on the topic of iodine deficiency as being related to autism from Sullivan & Maberly**** as food for thought, bearing in mind I'm less inclined to believe there is just one factor linked to the increasing numbers of cases of autism being reported.

So, perhaps on that collected basis, there is a little more research to do when it comes to iodine and autism? Oh, and with my blogging caveat about no medical or clinical advice given or intended, please take some proper medical advice if you're thinking about supplementing with iodine (see here).

To close, The Life of Riley by the Lightning Seeds (not to be confused with the life of Whiteley).

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* Hamza RT. et al. Iodine Deficiency in Egyptian Autistic Children and Their Mothers: Relation to Disease Severity. Arch Med Res. 2013 Oct 9. pii: S0188-4409(13)00222-1. doi: 10.1016/j.arcmed.2013.09.012.

** Delange F. et al. Determining median urinary iodine concentration that indicates adequate iodine intake at population level. Bulletin of the World Health Organization. 2002; 80: 633-636.

*** Blaurock-Busch E. et al. Toxic Metals and Essential Elements in Hair and Severity of Symptoms among Children with Autism. Maedica (Buchar). 2012 Jan;7(1):38-48.

**** Adams JB. et al. Analyses of toxic metals and essential minerals in the hair of Arizona children with autism and associated conditions, and their mothers. Biol Trace Elem Res. 2006 Jun;110(3):193-209.

***** Sullivan KM. & Maberly GF. Iodine deficiency as a cause of autism? BMJ. Rapid Response. 13 October 2004.

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Hamza RT, Hewedi DH, & Sallam MT (2013). Iodine Deficiency in Egyptian Autistic Children and Their Mothers: Relation to Disease Severity. Archives of medical research PMID: 24120386

Autism and the thyroid

The thyroid has been mentioned quite a bit in the media and science circles this year. Following the catastrophic effects of the earthquake and tsunami in Japan this year, images of the Fukushima Daiichi nuclear plant going into meltdown were projected across the world. The fear was that because radioactive particles of iodine (and quite a few other things) have been released and given that thyroid cells are the only cells in the body that absorb iodine, there might be some risk. A similar effect seemed to be realised after the Chernobyl meltdown where rates of thyroid cancer roundabout shot up.

The thyroid is a small gland in the neck whose key job is to convert iodine into thyroid hormones. These thyroid hormones in turn regulate the metabolism of things like proteins, fats and carbohydrates and energy and metabolic processes. The main thyroid pre-hormone is thyroxin (T4) which in the liver is activated to triiodothyronine (T3), the active hormone. Smallish amounts of other hormones are also formed in the thyroid gland. Thyrotrophin releasing hormone (TRH) is released from the hypothalamus when T3 and T4 levels drop, which in turn asks the anterior pituitary to release thyroid stimulating hormone (TSH) to release more T3 and T4. Another good example of our amazing bodily feedback capabilities.

When things go wrong with the thyroid it normally goes one of two ways: hypothyroidism, where hormone production is lower than it should be (primary or secondary), or hyperthyroidism, where lots of hormone is produced. Graves' diseases is an autoimmune condition and a common form of hyperthyroidism.

OK thyroid 101 is over. What about any connection to autism spectrum conditions?

A fairly recent paper by Hoshiko and colleagues* adds to what is a small but growing body of work examining the thyroid and its minion hormones in relation to autism. Based on the combined strength of two study groups based in California, USA, 544 cases of autism were compared with 784 matched controls, and an elevated risk of autism was suggested where T4 levels were very low. The caveat to this statement is that significance was only reached for one cohort born in 1995. Remember T4 is the prehormone.

I have touched upon thyroid function and autism before on this blog. In that post, there was a suggestion of a link between autism and flame retardant materials containing PBDEs. Looking at the other research in this area, the results could best be described as mixed. This paper for example, again examining neonatal thyroxine levels in various neurodevelopmental conditions failed to find any significant association. Indeed quite a few of the earlier studies in this area reported no overall association between thyroid hormone concentrations and autism despite some individual cases potentially being linked.

That being said, don't rule out any thyroid connection just yet. Jim Adams and colleagues reported a 45% reduction in iodine levels in their cohort of children with autism which they speculated might tie into some problems with thyroid function (see here for an overview of iodine deficiency). This finding was part of a wider issue with other elements and perhaps mirrors similar problems recently reported on. Likewise this paper suggested that for those cases of autism where regression was reported, there might be an association with a family history of autoimmune thyroid disease. I have a post scheduled soon on the regression/brain overgrowth findings in autism reported recently; perhaps thyroid issues should form part of further phenotypic investigations?

With these collected research in mind, together with other 'possible' connections such as thyroid function and reelin (mentioned in autism research), I wouldn't necessarily close the book on any links between autism and thyroid function just yet. Indeed the link between the thyroid and psychiatry is just starting to get quite interesting..

* Hoshiko S. et al. Are thyroid hormone concentrations at birth associated with subsequent autism diagnosis? Autism Research. August 2011.