Altered ghrelin levels in boys with autism

"Honey, it's the '90s, remember?"

Saudi Arabia and autism research? It must be at least one author from the research tag-team that is Mostafa and Al-Ayadhi.

Indeed, in today's post it is Laila Al-Ayadhi featured on the paper by Felwah S. Al-Zaid and colleagues [1] (open-access) who concluded on: "a potential role for the hormone ghrelin in the pathogenesis of autism".

Ghrelin, by the way, is often called the 'hunger hormone' as a result of its effects in relation to energy homoeostasis. Alongside another hormone called leptin (which has also been implicated in cases of autism) the long-and-short of food intake regulation seem to be covered by these hormones [2].

The Al-Zaid paper is open-access but I'll direct you to a few important points...

• A case-control study, authors looked at various measures for 31 boys diagnosed with autism compared with 28 age- and sex-matched controls.
• Alongside various anthropometric measures, plasma and serum levels of "acyl ghrelin (AG), des-acyl ghrelin (DG), total testosterone (TT), free testosterone (FT), leptin and growth hormone (GH)" were measured. These were single spot measures with samples taken "after an overnight fast". 
• Results: the autism group were on average heavier than controls but aside from that, no other physical measure was significantly different (mean height was greater in the autism group but just escaped significance). Both acyl ghrelin and des-acyl ghrelin levels were significantly lower in the autism group. By contrast, leptin levels were higher in the autism group (as per other independent findings) and free and total testosterone levels were significantly elevated compared to controls. Taking into account the effect of weight and it's link to adiposity, authors also showed that an analysis of a smaller subgroup (autism, n=27; controls, n=28) where mean weight was controlled for, found a similar trend in hormone levels (see this link to Table 3 of the paper) bearing in mind how body fat can influence the parameters.
• Various correlational analyses were completed on the data but given the relatively small participant groups and the use of spot samples I'm not particularly minded to read too much into these findings at this time.
• The authors conclude that their study: "contributes significantly to the understanding of hormonal dysregulation in the pathophysiology of autism, as it provides baseline data regarding hormonal profiles in autism and substantiates potential clinical interventions".

Small participants numbers and a "lack of female subjects with autism" kinda prohibit me from reading too much into these findings as they stand. I've already made mention of the research trend when it comes to elevated leptin levels and autism (see the paper from Rodrigues and colleagues [3] as one example). Likewise, testosterone levels and autism have received quite a bit of autism research attention down the years (see here). Indeed, elevations in testosterone levels not described in-utero with some potential relationship to foetal programming, has been the stuff of controversy in autism research circles [4].

Going back to the primary ghrelin findings and the observations of lower levels detected in their autism group, the authors speculate on some of the hows and whys of their findings. Gastrointestinal (GI) issues get a call-out and how some of the variety of GI issues noted in cases of autism "could affect the gastric mucosa and interfere with the normal function of ghrelin-secreting cells". although no particulars about GI issues are included in their descriptions of their cohort. One additional issue that I would perhaps add to the whole inflammation, dysbiosis et al discussions would be how ghrelin seems to play some role in GI motility [5] too. That being said, 'wide-ranging' is perhaps the best way to describe what biological processes ghrelin might impact on [6].

I was a touch surprised that the more usual role for ghrelin in terms of hunger and energy homoeostasis was not given more prominence in the Al-Zaid article on autism. Food and feeding patterns are important topics when it comes to autism as per discussions on the extremes sometimes noted in cases of autism (see here) and the increasingly important issue of weight (see here) (which also seemed to be picked up in the authors' findings). One might speculate that hunger and signals linked to hunger might be similarly tied into at least some of the feeding issues reported in autism?

As I seem to do in many discussions these days, I'll reiterate that there is quite a bit more to see and do in research terms on the relationship between ghrelin and related hormones and autism. The additional suggestion from Ghanizadeh [7] about the ghrelin being a "promising therapeutic target for co-occurring autism and epilepsy" might also be worthy of greater inspection.

Music to close. Iggy Pop and Lust for Life.

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[1] Al-Zaid FS. et al. Altered ghrelin levels in boys with autism: a novel finding associated with hormonal dysregulation. Sci Rep. 2014 Sep 26;4:6478.

[2] Klok MD. et al. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007 Jan;8(1):21-34.

[3] Rodrigues DH. et al. Changes in Adipokine Levels in Autism Spectrum Disorders. Neuropsychobiology 2014;69:6-10

[4] Geier DA. & Geier MR. A prospective assessment of androgen levels in patients with autistic spectrum disorders: biochemical underpinnings and suggested therapies. Neuro Endocrinol Lett. 2007 Oct;28(5):565-73.

[5] Greenwood-Van Meerveld B. et al. Ghrelin as a target for gastrointestinal motility disorders. Peptides. 2011 Nov;32(11):2352-6.

[6] Delporte C. Structure and physiological actions of ghrelin. Scientifica (Cairo). 2013;2013:518909.

[7] Ghanizadeh A. Ghrelin as a promising therapeutic target for co-occurring autism and epilepsy. Epilepsy Behav. 2011 Feb;20(2):420-1.

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Al-Zaid FS, Alhader AA, & Al-Ayadhi LY (2014). Altered ghrelin levels in boys with autism: a novel finding associated with hormonal dysregulation. Scientific reports, 4 PMID: 25257829

Vitamin D and autism: a continuing saga

The "sunshine vitamin" that is vitamin D has cropped up quite a few times on this blog for all manner of reasons. The suggestion of a link (whatever that means) between vitamin D and the autism spectrum conditions has received the lion's share of coverage, be that in relation to measured levels of vitamin D (see here and see here) or more speculatively, the possible impact of something like deficiency of vitamin D to symptoms or physiology (see here and see here). I've also not been adverse to talking about the 'D' in relation to other conditions or states either (see here and see here).

Monet at dusk @ Wikipedia

Without trying to do a Linus Pauling on vitamin D [bearing in mind the pendulum potentially swinging partially his way], I am genuinely interested in how this stuff might show some connection to a condition like autism. Further, whether the reports of deficiency (as they invariably tend to show) reflect something important for core symptoms, or are tied into specific comorbidity [1] or are just purely epiphenomenal and reflective of a more widespread population deficiency [2]. A few papers add to my interest in this area, specifically from Dr John Cannell who heads the non-profit Vitamin D Council based in the US. For those of you who have started to use PubMed Commons, Dr Cannell is certainly putting this post-publication review option to very good use.

So, first up is the paper from Grant & Cannell [3] (open-access here) which looked at US autism prevalence estimates for 2010 "with respect to indices of solar UV-B (UVB) doses" according to state. Based on an analysis of prevalence estimates for autism coupled to variables such as ethnicity and geographical latitude, time of year and solar UVB doses, the authors concluded that "autism prevalence among those aged 6–17 y in 2010 was significantly inversely correlated with solar UVB doses". Further, they speculate about the effects of maternal vitamin D deficiency as a potentially important issue when it comes to offspring autism risk. There was some other media interest in these results at the time of publication in 2012.

Obviously I don't need to point out that this was a number-crunching paper which relies on a statistical association so one has to be quite careful of making too much of the findings. Yes, the authors looked at "other possible risk-modifying factors" such as air pollution (see here) and obesity (see here) but one needs always to be cautious when it comes to correlation (as in, not necessarily equalling causation). That also other researchers have downplayed the maternal vitamin D - offspring autism, sorry autistic traits, link (see here) is also important. Me being me though, I'm still interested in the Grant/Cannell findings, particularly when one considers that not-so-long-ago paper which looked at ADHD prevalence and solar intensity and the growing realisation that autism is probably not a stand-alone condition in terms of comorbidity.

Next up, another paper from Cannell & Grant [4] (open-access here) which is a rather more review type paper on the various biological processes which vitamin D is reported to be involved with and how these might link into autism. I'm not going to rehash the paper in its entirety because it is open-access. That being said, there are some familiar themes contained in the review - autoimmunity, mitochondrial issues, etc - which are all potentially important issues to at least some of the autisms. Picking out one detail however, which fell under the heading 'Comorbid Conditions' I was struck by the discussion about adiponectin levels with autism and vitamin D levels in mind. It may be a slightly off-the-wall thought but given mention of this adipokine and my recent interest in elevated leptin levels being reported in a fair few cases of autism I couldn't help but wonder whether there may be further investigations to be had on an effect of vitamin D in relation to leptin elevations [5] with an autism slant.

What I think is worth taking from these papers and the growing scientific interest in vitamin D and autism including that related to the issue of ethnicity and autism (see here) recently illustrated in the Somali-autism initiative, is that there is still much to do in this area of autism research. That vitamin D deficiency does seem to be an issue for some people with autism [6] should already imply that deficiency should be corrected, save any of the more classical problems coming about as a result [7].

Whether the effects of vitamin D extend further into autism and in particular, the presentation of autism or its suggested biological profile (see here for example), is something I'd like to see more on, with the promise of some potential answers already on the research horizon (see here and see here). Oh, and I should also mention the recent papers by Zhang and colleagues [8] and Patrick & Ames [9] too...

Smartphone vitamin D analysis anyone?

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[1] Anglin RE. et al. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013 Feb;202:100-7.

[2] Davies JH. et al. Epidemiology of vitamin D deficiency in children presenting to a pediatric orthopaedic service in the UK. J Pediatr Orthop. 2011 Oct-Nov;31(7):798-802.

[3] Grant WB. & Cannell JJ. Autism prevalence in the United States with respect to solar UV-B doses: An ecological study. Dermatoendocrinol. 2013 Jan 1;5(1):159-64.

[4] Cannell JJ. & Grant WB. What is the role of vitamin D in autism? Dermatoendocrinol. 2013 Jan 1;5(1):199-204.

[5] Long J. et al. 1,25-Dihydroxyvitamin D3 upregulates leptin expression in mouse adipose tissue. J Endocrinol. 2013 Jan 18;216(2):265-71.

[6] Duan XY. et al. Relationship between vitamin D and autism spectrum disorder. Zhongguo Dang Dai Er Ke Za Zhi. 2013 Aug;15(8):698-702.

[7] Stewart C. & Latif A. Symptomatic nutritional rickets in a teenager with autistic spectrum disorder. Child Care Health Dev. 2008 Mar;34(2):276-8.

[8] Zhang M. et al. Do children with mental disorders have higher prevalence of hypovitaminosis D? F1000Res. 2013 Jul 17;2:159.

[9] Patrick RP. & Ames BN. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB J. 2014 Feb 20

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Grant WB, & Cannell JJ (2013). Autism prevalence in the United States with respect to solar UV-B doses: An ecological study. Dermato-endocrinology, 5 (1), 159-64 PMID: 24494049

Plasma leptin levels and autism: a growing consistency?

Increased levels of leptin in cases of autism was a primary finding described in the paper by Rodrigues and colleagues [1] as part of their analysis of the adipokines, the cell signalling molecules secreted by fat (adipose tissue) (see this paper by Trayhurn and colleagues [2] for quite a good overview). Not for the first time I might add, that elevations in levels of leptin have been talked about with autism in mind [3]. Indeed if you want even more evidence of a possible link, see also the paper by Blardi and colleagues [4] and their findings in relation to cases of Rett syndrome [5]. Oh and elevations in leptin in cases of autism crosses countries too.

Have parasol will travel @ Wikipedia

From the beginning, leptin is an adipokine which are cytokines. There is quite a bit of chatter about leptin being more of a proinflammatory cytokine and in particular, it's similarity to another inflammatory-related cytokine, IL-6 (see here for a previous post on this molecule). It's also worthwhile noting that leptin has an emerging role in the shift in immune function toward a T-helper1(Th1) response (see here for some background on Th1 and Th2 responses) which potentially brings into play an autoimmune element. I've actually talked about leptin before on this blog and some preliminary findings correlating leptin levels and fatigue scores in cases of Chronic Fatigue Syndrome (CFS).

Quite a lot of discussion has focused on the role that leptin also plays in regulating dietary intake and its suggested link with body weight and obesity; circulating leptin levels correlating well with the proportion of body fat. It's well beyond the scope of this post or indeed my very rudimentary knowledge of this area, but there is quite a lot of evidence to suggest that deficiencies in leptin lead to severe obesity as a function of it's role in the activation of satiety mechanisms. That being said it's not all plain scientific sailing as per the review by Paracchini and colleagues [6] (open-access) on the genetics of leptin and obesity. Obese people generally have high leptin levels, as a function of having more fat, which has led to some speculation about the notion of leptin resistance (see the paper from Myers and colleagues [7] for more information).

That energy homeostasis role aside - which may nevertheless be important when it comes to medication-induced weight gain in autism [8] - the elevations in plasma leptin levels reported by Rodrigues et al (and other authors) may be important. As per the Stringer paper [9] which was the source material for my leptin-CFS post: "Multiple studies have demonstrated elevated levels of circulating leptin in chronic inflammatory conditions". A quick trawl of PubMed leads me to believe that there may be indeed be an important role for leptin in the process of inflammation as per articles like this one and this one. That also quite a nice correlation between leptin and more traditional markers of inflammation, such as C-reactive protein (CRP) have been discussed [10] is added fodder for this assertion. Oh, and just in case you're wondering, CRP has also been examined with autism in mind (see this post and this post).

The implication therefore is that elevated levels of leptin present in cases of autism might be an important sign of immune processes, particularly those related to inflammation. I can't say whether this means autism per se is 'inflammatory' in those cases of elevations or whether we're talking about some inflammatory-mediated comorbidity for example. Nonetheless, there is a growing consistency in the results obtained so far which is crying out for more detailed investigation controlling for weight, body fat and body mass index (BMI). This call likewise resonates with other conditions too including bipolar disorder and schizophrenia albeit without over-generalising and again taking into account the important effect of medication.

And just in case you're wondering about possible ways and means to reduce leptin levels, well without any medical or clinical advice being given, how about a spot of exercise for starters?

To close, having recently watched the excellent Dave Grohl documentary about Sound City (UK viewers if they're quick, can catch it on the BBC iPlayer), a song about someone's wife calling?

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[1] Rodrigues DH. et al. Changes in Adipokine Levels in Autism Spectrum Disorders. Neuropsychobiology 2014;69:6-10

[2] Trayhurn P. et al. Adipose Tissue and Adipokines—Energy Regulation from the Human Perspective. J Nutr. 2006; 136: 19355-19395.

[3] Ashwood P. et al. Brief report: plasma leptin levels are elevated in autism: association with early onset phenotype? J Autism Dev Disord. 2008 Jan;38(1):169-75.

[4] Blardi P. et al. Variations of plasma leptin and adiponectin levels in autistic patients. Neurosci Lett. 2010 Jul 19;479(1):54-7.

[5] Blardi P. et al. Long-term plasma levels of leptin and adiponectin in Rett syndrome. Clin Endocrinol (Oxf). 2009 May;70(5):706-9.

[6] Paracchini V. et al. Genetics of Leptin and Obesity: A HuGE Review. Am. J. Epidemiol. 2005; 162: 101-114.

[7] Myers MG. et al. Obesity and Leptin Resistance: Distinguishing Cause from Effect. Trends Endocrinol Metab. 2010 November; 21(11): 643–651.

[8] Nurmi EL. et al. Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies. Transl Psychiatry. 2013 Jun 25;3:e274.

[9] Stringer EA. et al. Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. Journal of Translational Medicine 2013, 11:93

[10] Shamsuzzaman ASM. et al. Independent Association Between Plasma Leptin and C-Reactive Protein in Healthy Humans. Circulation. 2004;109:2181-2185.

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Rodrigues D.H, Rocha N.P, Sousa L.F.C, Barbosa I.G, Kummer A, & Teixeira A.L (2013). Changes in Adipokine Levels in Autism Spectrum Disorders Neuropsychobiology

Fatigue severity and serum leptin levels in chronic fatigue syndrome

In the very complicated world of medical research and science, the days of one chemical, one metabolite, or one gene driving and sustaining ill-health and particular diseases or conditions seem to be all but long past. Sure, there are conditions which on the surface seem to be driven by only one factor, but more often than not is the realisation that we humans are very complicated creatures indeed.

Leptin @ Wikipedia  

I was therefore interested to read the paper by Elizabeth Stringer and colleagues* (open-access) describing the results from a small cohort of women diagnosed with chronic fatigue syndrome (CFS) looking at potential biological correlates which might accompany day-to-day changes in the severity of fatigue experienced by participants.

Yes, I'm back with CFS to add to my ramblings about gut bacteria, mitochondrial disorder, amino acids. Bear with me...

The paper is open-access but a few pointers might be useful:

• It was an interesting methodology the authors adopted which saw 10 women diagnosed with CFS and 10 asymptomatic age- and BMI-matched controls asked to monitor their fatigue-related behaviours over the course of 25 days.
• This self-report was accompanied by a professionally taken daily blood draw (yes, 25 days of giving a blood sample!) which were subsequently analysed for various cytokines - 51 in all.
• The self-report data and pattern of cytokine levels were analysed, correlated and networked (using a machine learning algorithm).
• Results: "Six participants with CFS and one healthy control demonstrated significant positive correlations between fatigue and leptin". Leptin by the way is a hormone normally implicated in the in-and-out process of energy expenditure, so potentially relevant to a condition like CFS which is characterised by fatigue.
• Buoyed by their leptin results, the authors also report that with the help of that Weka’s LibLINEAR algorithm, they were able to use the suite of cytokine results to distinguish 'high' and 'low' fatigue days for the CFS group with 78.3% accuracy compared with just above chance level in the asymptomatic control group. "The CFS model correctly identified 77.8% of the low fatigue days and 78.9% of high fatigue days".
• Ergo cytokines and inflammation seem to be not only tied into CFS pathology but might actually be overlap with the ebb and flow of clinical symptoms on a day-to-day basis.

You can perhaps see how this study might be an important one for CFS. Given the connection between leptin (energy) and CFS, you might be saying to yourself that this sounds all very logical so why did no-one look at the possible connection before? Well, they did, or rather Cleare and colleagues** did and concluded: "we found no evidence of alterations in leptin levels in CFS" despite some potential effects from low dose hydrocortisone therapy on leptin levels under placebo-controlled conditions.

This is not by any means the first time that immune function has cropped up on the CFS research radar (see this post) and probably won't be the last either. I don't however want to speculate too much more on these results without them being subject to appropriate replication with a larger patient set and that all-important diagnostic criteria being standardised. The XMRV story (see here) still lingers in the mind, as do other controversies on the CFS landscape such as Ampligen and Rituximab.

To close, a song about a dirty old town.

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* Stringer EA. et al. Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity
in chronic fatigue syndrome: evidence of inflammatory pathology. Journal of Translational Medicine. 2013; 11: 93.

** Cleare AJ. et al. Plasma leptin in chronic fatigue syndrome and a placebo-controlled study of the effects of low-dose hydrocortisone on leptin secretion. Clin Endocrinol (Oxf). 2001; 55: 113-119.

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Stringer, E., Baker, K., Carroll, I., Montoya, J., Chu, L., Maecker, H., & Younger, J. (2013). Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology Journal of Translational Medicine, 11 (1) DOI: 10.1186/1479-5876-11-93