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Tuesday, 16 January 2018

How much Histidine? Dermatitis and FLG mutations


Today’s post is not about autism, it is about allergy and atopic dermatitis in particular.
Many people are affected by atopic dermatitis (AD), also known as eczema; it is particularly common in those with autism. Children who develop asthma have often first developed atopic dermatitis (AD).
Atopic Dermatitis is another of those auto-immune conditions and the sooner you stabilize such conditions the better the prognosis.




Skin therapies from a company
spun-off from Manchester University


Histidine
A while back on this blog I was looking at the various amino acids and came across the observation that histidine, a precursor of histamine, appears to be a mast cell stabilizer. Mast cells are the ones that release histamine and IL-6 into your blood. Histamine then does on the trigger yet more IL-6 to be produced.  IL-6 is a particularly troublesome pro-inflammatory cytokine.
At first sight giving a precursor of histamine to people who want less histamine seems a crazy thing to do, but plenty of people report their allergies improving after taking histidine. As we have discovered, feedback loops are very important in human biology and these can be used sometimes to trick the body into doing what you want it to do. Having a higher level of histidine in your blood might make histamine production easier but it might also be telling the body not to bother, or just to delay mast cells from degranulating.  Whatever the mechanism, it does seem to work for many people. 

How Much Histidine?
Most histidine pills are 0.5g and it appears people use about 1g to minimize their allergy. 1g is the dose Monty, aged 14 with ASD, has been using during the pollen allergy season.
My sister recently highlighted a new "high tech" OTC product for skin conditions, Curapella/Pellamex, its main ingredient is histidine and it is a lot of histidine, 4g.




The company that produces the supplement have teamed up with the Universities of Edinburgh and Manchester to make a clinical trial, which is featured below.
They are considering the interaction between histidine and filaggrine (produced by the FLG gene). 

Mutations in the FLG gene are associated with atopic dermatitis and indeed with asthma, hay fever, food allergies, and, rather bizarrely, skin sensitivity to nickel.
In effect it is suggested that histidine makes filaggrine work better and thus atopic dermatitis and some other skin conditions will improve.  



Atopic dermatitis (AD), also known as eczema, is one of the most common chronic skin conditions worldwide, affecting up to 16% of children and 10% of adults. It is incurable and has significant psychosocial and economic impacts on the affected individuals. AD etiology has been linked to deficiencies in the skin barrier protein, filaggrin. In mammalian skin, l-histidine is rapidly incorporated into filaggrin. Subsequent filaggrin proteolysis releases l-histidine as an important natural moisturizing factor (NMF). In vitro studies were conducted to investigate the influence of l-histidine on filaggrin processing and barrier function in human skin-equivalent models. Our further aim was to examine the effects of daily oral l-histidine supplementation on disease severity in adult AD patients. We conducted a randomized, double-blind, placebo-controlled, crossover, nutritional supplementation pilot study to explore the effects of oral l-histidine in adult AD patients (n=24). In vitro studies demonstrated that l-histidine significantly increased both filaggrin formation and skin barrier function (P<0 .01="" respectively="" span="" style="background: yellow; margin: 0px;">Data from the clinical study indicated that once daily oral l-histidine significantly reduced (P<0 .003="" 34="" 39="" 4="" ad="" after="" and="" assessment="" by="" disease="" eczema="" measure="" of="" oriented="" patient="" physician="" scoringad="" self-assessment="" severity="" span="" the="" tool="" treatment="" using="" weeks="">. No improvement was noted with the placebo (P>0.32). The clinical effect of oral l-histidine in AD was similar to that of mid-potency topical corticosteroids and combined with its safety profile suggests that it may be a safe, nonsteroidal approach suitable for long-term use in skin conditions that are associated with filaggrin deficits such as AD. 
In this paper, we suggest that a simpler, nutritional supplementation of l-histidine may have a beneficial potential in AD.

l-histidine is a proteinogenic amino acid that is not synthesized by mammals. In human infants, it is considered “essential” due to low levels of histidine-synthesizing gut microflora and minimal carnosinase activity, which helps in releasing free l-histidine from carnosine.24 Our interest in the use of l-histidine in AD was stimulated by several observations. Firstly, in both infants and adults, a histidine-deficient diet results in an eczematous rash.25 In rodents, 3H-histidine is rapidly (1–2 hours) incorporated into profilaggrin within keratohyalin granules after intraperitoneal or intradermal injection14,26 and within 1–7 days is released as a free NMF amino acid in the upper stratum corneum.14 Furthermore, reduced stratum corneum levels of free NMF amino acids, including histidine and its acidifying metabolite urocanic acid (UCA), are associated with AD disease severity and FLG genotype.27,28

Given this evidence for the dependence of filaggrin processing and NMF formation on suitable levels of l-histidine, we hypothesized that l-histidine would both enhance filaggrin processing in an in vitro, organotypic, human skin model and have beneficial effects as a nutritional supplement in subjects with atopic dermatitis. 

After a 2-week wash-out period in which subjects were asked not to use any medicinal product for their AD, the same measures were repeated and patients were provided with identical sachets containing either 4 g l-histidine (Group A) or 4 g placebo (erythritol); Group B) which was taken once a day, dissolved in a morning fruit drink.  





Conclusion

It looks like 4g of histidine has the same potency as mild topical steroid creams, when treating atopic dermatitis.
The big problem with topical steroids is that you can only use them for a week or two. It you use them for longer, you end up with a bigger problem than the one you were trying to treat.
The 4g a day of histidine is put forward as a safe long term therapy.
Is the mode of action related to mast cells or filaggrin (FLG)? Or perhaps both?
If 1g of histidine does improve your allergies, perhaps you should feel free to try a little more.
You can buy histidine as a bulk powder. Pellamex is quite expensive, particularly if more than one family member is affected, as you would expect to find in a genetic condition.  




15 comments:

  1. Hi Peter,
    Is histidine effective for psoriasis ?

    Thanks Liz

    ReplyDelete
    Replies
    1. Liz, psoriasis is an autoimmune condition where many things seem to be partially effective in different people.

      Histidine might help and if bought as a powder is not expensive, so worth a try. I think Quercetin, also inexpensive, should help and there is a recent animal study supporting its use.

      Quercetin ameliorates imiquimod-induced psoriasis-like skin inflammation in mice via the NF-κB pathway.
      https://www.ncbi.nlm.nih.gov/pubmed/28499194

      Some of those immuno-modulating probiotic bacteria are likely to help. The really expensive one, VSL#3, helps some people.

      Delete
  2. Peter, can you add some info on Verapamil ? I had a long conversation with my son's neuro today and he says he's not opposed to it as long as I can produce two or more studies that it can combat inflammation !!! (My son has had chronic urticaria since December 2015 and I don't want to start the Bumetanide until his hives resolve).

    I looked on PubMed but wasn't too successful on Verapamil as a potent anti-inflammatory (he wants to see clinical trials with dosages).

    This is a difficult man and the fact that he's even having this conversation with me is huge and I don't want to put my foot in my mouth again (I suffer from chronic foot-in-mouth-itis, wish there was a cure for that).

    Thank you for any help you can give me in sourcing the studies on Verapamil. Much obliged.

    ReplyDelete
    Replies
    1. GRT, I am advocating Verapamil as a therapy for allergy-induced autism flare-ups (anxiety, SIB, headaches etc) rather than for the allergy itself. At the dose I use, it does not relieve the symptoms of the allergy.

      I have been informed that in some people at higher doses it is as effective as an H1 antihistamine. I would use the antihistamine.

      Mast cells degranulate and release histamine. One way to stabilize mast cells is to block the calcium channels they have that play a role in the degranulation process. Verapamil is such an L-type calcium channel blocker.

      The paper below shows that 35 years ago it was found that verapamil can relieve allergy induced asthma.

      Effect of verapamil on allergen-induced asthma in patients with respiratory allergy.
      https://www.ncbi.nlm.nih.gov/pubmed/6881608

      Verapamil may indeed help you son's urticaria, but first use the standard mainstream therapies. (H1 antihistamines, Montelukast/Singulair and if all else fails a course of steroids).

      I would concentrate on showing the neurologist that verapamil has effects inside the brain.

      Outside of this blog the interest is mainly in bipolar.

      A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030455/

      Delete
    2. Peter, I am looking at Verapamil because you had said a while ago that kids with known inflammatory conditions seem to have high intracellular chloride levels and that this appears to render the Butanemide "ineffective".

      That is my main interest in the Verapamil. Given his chronic urticaria, I thought it best to dose Verapamil for a couple of months to reduce potential high intracellular chloride levels, before getting started on the Bumetanide.

      Please advise ? I am not the sharpest knife in the drawer but need to understand this to help my son -- idiopathic autism with no language at age 8. Cognitively severely impaired. Multiple MRIs show "normal", but his EEGs show SEDs that aren't resolving despite a high dose of Topimirate.

      Thanks !!!

      Delete
    3. GRT. It is definitely a good idea to resolve known inflammatory conditions first.

      Inflammatory conditions make bumetanide's job worse, so much so that it can appear to stop working, in responders.

      I do not think Verapamil is the best drug to treat your son's urticaria. I think you should ask your regular doctor to treat it, using the well proven existing therapies.

      If your son had aggression, or self injurious behavior, that appeared with the urticaria, Verapamil might resolve those behaviors.

      So follow your doctor's advice to treat the urticaria and then make your bumetanide trial.

      Delete
  3. A new interesting study on prebiotics in infant pigs came out today which suggests supplementing formula with prebiotics can not only improve gut health, but brain function as well (at least in pigs):

    Press Release:

    https://www.sciencedaily.com/releases/2018/01/180117114916.htm

    Paper:

    http://www.tandfonline.com/doi/full/10.1080/1028415X.2017.1415280

    Now, the main interesting and accidental finding that I thought was relevant to autism was that in addition to showing improved profiles of Lactobacillus bacteria and butyrate production and a decrease of so-called volatile fatty acids which are thought to be bad for the brain was a decrease of brain serotonin levels as well in the brains of pigs as well. Too much brain serotonin early in life can not only cause a changed developmental trajectory in the brain itself, but also downregulate serotonin receptor development, thereby potentially leaving the brain with too few serotonin receptors later on in development, thereby reducing serotonin sensitivity and signaling.

    With respect to autism, hyperserotonemia is a commonly debated biomarker and it might just be that issues with prebiotics being available in breast milk from poor maternal diet and other environmental factors such as stress as well as the increasing prevalence of formula feeding in western children could be contributing factors to hyperserotonemia in some children (this hypothesis is a stretch but nevertheless I think is worth thinking about).

    ReplyDelete
    Replies
    1. Tyler, it is interesting that there is so much interest in these indigestible fibers as a means to improve gut microbiota.

      We have seen that the immune system seems to be conditioned very early in life and that gut bacteria play a key role in this. So giving these fibers to those babies who are not fed by mothers milk seems a very smart idea.

      The effect of these bacteria seems to continue in later life, but to a lesser extent, you cannot easily "reset" a mal set up immune system.

      The two fiber in your study (Polydextrose and Galactooligosaccharide) and Inulin are interesting and may well be worth supplementing, particularly in those people who lack fiber in their diet.

      You either increase fiber, add the probiotic bacteria or add the substance that you wanted to be produced in the gut (like butyric acid).

      The tips though are simple, keep a pet dog inside the house during pregnancy (source of "good" bacteria) and do not use formula milk.

      Delete
    2. Actually I think GOS (galactooligosaccharide) is already in some baby formulas.

      /Ling

      Delete
    3. It will probably be a while before formula milk becomes as good as the real thing in terms of long-term health outcomes and may someday end up being superior, but that is likely a long ways off based upon all the new stuff being explored with regards to all the nutrients in breast milk that were previously written off as inconsequential and now based on the latest research seem to be integral to the health of the baby. My wife did not last long with breastfeeding, so I sometimes have those moments where I wish I could send a message back into the past to change a few things we now know are critically important to the health of the baby and could of substantially reduced the risk of autism.

      Delete
    4. I breastfed both my kids for 4 years. My son with autism actually had to be weaned forcibly because we started an ABA program by then and the BCBA felt that 4 was too old to still be nursing. He also had healthy, balanced meals (picky eating did not start until age 5) and the nursing was mostly a comfort thing after age 1.

      I had a healthy diet with my pregnancies but severe stress in the second trimester with my son.

      Why did this happen to my son ? Was it the severe stress ?

      Delete
    5. GRT, stress is indeed a risk factor, but most autism is a combination of many factors; some of these you can control and some you cannot.

      Delete
  4. Hi Peter

    Are you aware of reports of successful histidine use in people with systemic mast cell activation e.g. mastocytosis/MCAS or other multiorgan mast cell dysfunction manifestations?

    I wonder if this feedback loops involving mechanism of action of histidine will work as well in persons with mast cell degranulation of -probably - much higher degree than in allergy.

    Does histidine supplementation effect has any association with histamine blood level?

    ReplyDelete
    Replies
    1. Agnieszka, I never found much research into histidine, which is disappointing, just the odd finding that many people find it helpful for allergy. A dose of 1mg does have a positive effect on Monty's pollen allergy, I think a dose of 4mg would have a larger effect. If 4mg is a safe long term dose, as it appears to be, I think it is worth testing on any mast cell dysfunction.

      Delete
    2. If there is no research, then it would be interesting to hear from people with mast cell activation disorder if histidine was found helpful for MCAD and in what dose.

      1 mg did not prevent odd behavioral flare in my son few months ago, which later resolved on Benadryl + Ranitidine, so I guess it was mast cell activation driven. I am not sure if using 4 mg would be of help or rather too risky.

      Delete

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