Vitamin A supplementation and autistic symptoms: hidden away but no significant effect...

I used the words 'hidden away' in the title of this post because I had a bit of a time deciphering the findings reported by Juan Liu and colleagues [1] (open-access) investigating "the role of VA [vitamin A] in the changes of gut microbiota and changes of autism functions in children with ASD [autism spectrum disorder]." Vitamin A by the way, is a fat soluble vitamin involved in various process such as immune function and vision health. There is a darker side to vitamin A however, as safe upper limits have been in place for quite a few years, particularly for pregnant women as a result of potential teratogenic effects.

Suffice to say that after 6 months of VA supplementation - "participants with an insufficient plasma retinol status (<1.05 μmol/L) received VAI [vitamin A intervention?] with a dose of 200,000 IU once orally" - the authors reported seeing no significant changes in autistic signs and symptoms as measured before and after using the Autism Behavior Checklist (ABC), Childhood Autism Rating Scale (CARS) and Social Responsiveness Scale (SRS). They did however report changes in retinol status (a marker for vitamin A availability) coinciding with supplementation: "The plasma retinol level increased from 0.59 ± 0.19 μmol/L to 0.72 ± 0.20 μmol/L in the group of 64 after 6 months of VA supplementation" and changes in the percentages of vitamin A levels (typical, marginal deficiency, deficient) across their group. I say this however, based on their use of high performance liquid chromatography (HPLC) with photodiode-array detection for assaying for retinol; state-of-the-art about 30 years ago and now superseded by better detection technology such as mass spectrometry...

No mind, Liu et al also looked at "CD38 and acid-related orphan receptor alpha (RORA) mRNA levels" as "autism-related biochemical indicators’ changes" following supplementation. RORA - retinoic acid-related orphan receptor-alpha - has some research history discussed before on this blog (see here). Authors reported that: "After 6 months of intervention, plasma retinol, CD38 and RORA mRNA levels significantly increased" despite the seeming lack of effect on presented autistic symptoms.

Further: "Fresh stool samples were collected from participants who did not receive supplemental probiotics or prebiotics and who were not treated with antibiotics for the previous 1 month." Said poo(p) samples - pre and post-vitamin A supplementation - were analysed alongside food diaries and food frequency behaviours. Authors observed that bacterial species showed changes between the baseline and post-intervention samples; specifically settling on "significant increases in the proportion of Bacteroidetes/Bacteroidales and decreases in Bifidobacterium after the VAI, accompanying significant increases in autism biomarkers, while no significant changes were observed in autism symptoms."

What can we make of these collected findings? Well, whilst vitamin A deficiency is something to look out for among children with autism [2] (see here too) and previous research has indicated "an empirical basis for the development of a pharmacological ASD treatment strategy based on retinoids" [3] the lack of a significant behavioural effect from vitamin A supplementation in this case cannot be just glossed over. Yes, this was an open-trial - "we aimed to conduct a placebo-controlled intervention study, but all the participants showed an insufficient VA status and were thus enrolled into the VAI group" - and so has shortcomings but the findings of a lack of significant change across any and all of the autism-related behaviour schedules used is notable. The biological results are a little more interesting; particularly the bacterial findings. But again it wouldn't be difficult to say 'so what?' to such bacterial results given that no corresponding changes in autistic behaviour(s) were noted...

----------

[1] Liu J. et al. Effect of vitamin A supplementation on gut microbiota in children with autism spectrum disorders - a pilot study. BMC Microbiology. 2017; 17: 204.

[2] Chiu M. & Watson S. Xerophthalmia and vitamin A deficiency in an autistic child with a restricted diet. BMJ Case Rep. 2015 Oct 5;2015. pii: bcr2015209413.

[3] Riebold M. et al. All-trans retinoic acid upregulates reduced CD38 transcription in lymphoblastoid cell lines from Autism spectrum disorder. Mol Med. 2011;17(7-8):799-806.

----------

ADHD and vitamin levels

"ADHD [attention-deficit hyperactivity disorder] patients were overrepresented in the group with low levels of some vitamins, possibly indicative of inadequate dietary intake of these micronutrients in a subgroup of patients. It is important to identify these patients in dietary intervention trials of ADHD."

So said the study findings reported by Elisabeth Toverud Landaas and colleagues [1] (open-access) providing some potentially important data on how nutritional factors might intersect with the diagnosis of ADHD. So: "Owing to the important and neurologically relevant functions of vitamins and the lack of studies exploring this topic in ADHD, we measured serum levels of the major vitamin classes in a sample of adult ADHD patients and controls to determine whether vitamin levels are associated with ADHD diagnosis and psychiatric symptoms." Said participants (n=133) were young adults and most were listed as having ADHD according to a "Norwegian national registry of adult ADHD patients." Vitamin levels were assessed from blood samples and compared with results for 131 control participants as per other studies on this cohort from this authorship group [2]. It's worth pointing out that samples were in deep freeze storage for between 2-9 years between collection and thawing for analysis.

Various vitamins were measured in those samples (vitamins A, B6, , B9, B12 and D to name a few) alongside levels of cotinine "to assess [tobacco] smoking status." The analytical assay(s) of choice was, in the most part, a familiar one to this blog: liquid- or gas chromatography-tandem mass spectrometry.

Results: "The concentrations of vitamins B2, B6 and B9 were all significantly lower in the ADHD group." When results were analysed according to percentiles based on blood levels of the various vitamins results similarly showed that those with ADHD were 'over-represented' in the lower levels bandings of those previously described vitamins. Smokers, as defined by a "widely used cut-off of 80 nmol/L" of blood cotinine, were also over-represented in the ADHD group (66%) compared with control participants' samples (12%). The authors reported that: "vitamin B6 and B9 levels were significantly higher in non-smoking ADHD patients compared with smokers" suggesting that lifestyle choices may play a role in some of the results obtained. Finally, when it came to looking at any possible association(s) between measured vitamin levels and behaviours pertinent to ADHD (derived from responses to the Adult ADHD Self-report Scale (ASRS), the authors report some preliminary observations but I'd like to see a little more data before anything further is made of this.

These are interesting results (aren't they always!). I note that the authors make reference to the findings reported by Julia Rucklidge and colleagues on a vitamin-mineral mix for ADHD (see here) and the idea that correcting vitamin deficiencies might have effects beyond just the somatic. There are however caveats to the latest results: "The reason why we observed association between lower levels of some vitamins and ADHD is uncertain and probably multifactorial. Regrettably, we do not have information on lifestyle and nutrient intake from the participants to help in the interpretation of our observations. It is reasonable to think that differences in dietary factors may partly be responsible for the differences." Indeed.

There is also one final observation to touch upon in the Landaas results concerning the vitamin/hormone of the hour: vitamin D. Although there was no overall difference in vitamin D concentrations in the ADHD and not-ADHD group samples, the authors did observe that: "for vitamin D, ADHD patients were significantly overrepresented both in the lowest and highest 10th percentile groups." Bearing in mind past research has suggested that ADHD might be yet another diagnosis/label where vitamin D deficiency might be a feature (see here) it is pertinent that the authors suggest: "One reason for the overabundance of ADHD patients in the highest 10th percentiles of vitamin D may thus be that relatively more ADHD patients take vitamin D supplements, either as part of an experimental treatment of symptoms or as a consequence of a diagnosed vitamin D deficiency."

Finally: "It is possible that low levels of certain vitamins may contribute to ADHD symptoms. Dietary intervention trials have shown promising effects in ADHD. Thus, identification and correction of low vitamin levels could be beneficial in treatment of ADHD. Further studies are warranted for replication and for examination of the underlying mechanisms."

----------

[1] Landaas ET. et al. Vitamin levels in adults with ADHD. BJPsych Open. 2016 Dec 13;2(6):377-384.

[2] Aarsland TI. et al. Serum concentrations of kynurenines in adult patients with attention-deficit hyperactivity disorder (ADHD): a case-control study. Behav Brain Funct. 2015 Nov 5;11(1):36.

----------

Landaas ET, Aarsland TI, Ulvik A, Halmøy A, Ueland PM, & Haavik J (2016). Vitamin levels in adults with ADHD. BJPsych open, 2 (6), 377-384 PMID: 27990293

More extremes of a limiting diet and autism

In a previous post a while back, I discussed some examples in the peer-reviewed literature of where a self-limiting diet in the extreme can lead to with autism in mind. Today, I'm adding a further example of what food faddism might mean, to further forward the point that "a low threshold for vitamin level testing should be undertaken in autistic spectrum disorder cases, highlighting the importance of enquiring about dietary habits."

That last quote comes from the paper in question by Emma Duignan and colleagues [1] (open-access available here) who describe two case reports of teenagers with autism "with a background of moderate autistic spectrum disorder who were diagnosed with a multivitamin deficiency, including vitamin A." Said nutritional deficiency manifested as ophthalmic issues - relating to the physiology of the eye - that importantly seemed to abate following vitamin supplementation.

Aside from the idea that several factors might align to bring a person diagnosed with autism to a deficiency state, I was interested in the Duignan results for a few other reasons. I've talked about vitamin and mineral deficiencies a few times on this blog; more generally as per the results from Jim Adams and colleagues back in 2011 (see here) following the publication of their double-blind, placebo-controlled trial of supplementation through to more specific issues with something like the vitamin-of-the-hour, vitamin D (see here) or even the scurvy-preventer that is vitamin C (see here). There is quite a bit of literature out there to suggest that particularly in cases where dietary issues are noted to accompany a diagnosis of autism or autism spectrum disorder (ASD), one perhaps should expect nutritional deficiencies to follow.

The other thing that struck me about the Duignan results was the focus on ophthalmic issues as manifestations of those vitamin deficiency issues. It's not new news that among the various effects linked to something like vitamin A deficiency for example, vision and eye health may suffer. Although still in need of quite a bit of research, issues related to the eyes and knock-on effects for things like visual perception are no stranger to autism research as per my ramblings about the findings reported by Ikeda and colleagues [2]. The paper from Pineles and colleagues [3] on optic neuropathy due to vitamin B12 deficiency in cases of autism is also worth mentioning at this point and the question of whether at least some of the visual perceptual issues discussed with autism in mind might have a nutritional link?

We don't currently know how widespread nutritional deficiencies are when a diagnosis of autism is received because, at the moment, this is not something that is routinely tested for. On the basis of the Duignan and other results, I'd be minded to repeat my suggestion that where dietary issues are present for people on the autism spectrum, modern medicine could do a lot worse than find out whether there may be biological effects to come from a limited or restricted diet save any further charges of health inequality being levelled...

Music to close. Paul Simon - Me and Julio Down by the Schoolyard.

----------

[1] Duignan E. et al. Ophthalmic manifestations of vitamin a and d deficiency in two autistic teenagers: case reports and a review of the literature. Case Rep Ophthalmol. 2015 Jan 24;6(1):24-9.

[2] Ikeda J. et al. Brief report: incidence of ophthalmologic disorders in children with autism. J Autism Dev Disord. 2013 Jun;43(6):1447-51.

[3] Pineles SL. et al. Vitamin B12 optic neuropathy in autism. Pediatrics. 2010 Oct;126(4):e967-70.

----------

Duignan, E., Kenna, P., Watson, R., Fitzsimon, S., & Brosnahan, D. (2015). Ophthalmic Manifestations of Vitamin A and D Deficiency in Two Autistic Teenagers: Case Reports and a Review of the Literature Case Reports in Ophthalmology, 6 (1), 24-29 DOI: 10.1159/000373921