2013年7月11日木曜日

The bankrupt of the regulation of cortisol level in the skin tissue might be the essence of TSA.

Recently it has been revealed that epidermal cells produce cortisol (corticosteroid) by themselves. Topical steroid addiction (TSA) is considered to be related with the skin atrophy which causes the barrier dysfunction. The bankrupt of the regulation of cortisol concentration in the skin tissue might be its ground.

 The concentration of cortisol in the skin tissue is kept lower than in the blood.
 According to the following article about thermal injured patients, for example, plasma total cortisol took the value of 8.8μg/dl, free (protein unbound) cortisol 1.7μg/dl and tissue (skin) cortisol 0.74μg/dl.

 Measurement of tissue cortisol levels in patients with severe burns: a preliminary investigation.Cohen J et al, Crit Care. 2009;13(6):R189. Epub 2009 Nov 27.
   
 In healthy subjects as a control, the tissue cortisol was 0.20μg/dl. Only a fraction of the concentration in the blood is detected in the normal skin tissue outside the blood vessels and the value increases once inflammation such as burn occurs.

  By the way, epidermal cells, hair follicular cells and fibroblasts in the dermis can produce cortisol by themselves. What is more interesting is that the production of cortisol by those cells is amplified by the skin tissue cortisol. There is a positive feedback mechanism.


On the other hand, there is  also an enzyme that inactivates cortisol in the sweat gland. The concentration of cortisol in the skin tissue is controlled by those factors. The following figure is what is summarized.

11βHSD1 is an enzyme that converts cortisone (inactive steroid) to cortisol (active steroid) while 11βHSD2 is an enzyme that converts the latter to the former.
 What is the meaning of the positive feedback mechanism of cortisol production? It must be for the purpose of increasing the skin tissue concentration of cortisol rapidly in case of any inflammation such as burn occurs.

 If topical steroids are applied to the skin, epidermal cells or fibroblasts react to TS and produce cortisol. The increased cortisol effects to the cells themselves and suppress their own proliferation. In case of systemic steroids such as oral steroids, the effect to the skin tissue concentration is not so much because blood vessels regulate cortisol not to transfer too much to the skin tissue.

  Now you can understand how abnormal the situation of continuous use of topical steroids to the skin is. Physiologically the concentration of cortisol in the skin tissue is kept considerably low. Topical steroids violate the controlled situation.

 After stopping topical steroids, the epidermis becomes thicker than before TS application temporarily. It means the skin tissue lacks enough steroids temporarily.

 
1A:Before application of TS, 1B: thin epidermis after TS application, 1C 1D 1E: temporarily thickened epidermis after discontinuance of TS
(Morphologic Investigations on the Rebound Phenomenon After Corticosteroid Induced Atrophy in Human Skin. Zheng P, et al. J Invest Dermatol 82: 345-352, 1984)
 
 The fact that epidermis becomes thick means that the steroid deficiency has occurred. But what is the mechanism of the deficiency? There must have been too much steroids.
 
  One of the possible mechanism is as the following.

  11βHSD1/2 balance, which is 11βHSD1 dominant in the epidermal cells normally, changes to become11βHSD2 dominant after considerable dose of TS application.

 After discontinuance of TS, the skin tissue cortisol becomes low temporarily. Inactive form of steroid (cortisone ) is accumulated within the cell. After 11βHSD1 reactivation, skin tissue cortisol will be produced but from the accumulated cortisone. It never is a normal condition. The gene coding cortisol will not be up-regulated under such a condition and various proteins which are related to the gene will not  also be produced. So the skin remains fragile and the barrier dysfunction continues.

 It is only a hypothesis. However the temporarily deficiency of steroids after discontinuance must be explained in any way.  
 
 The below figure shows 11βHSD1/2 expression of the normal skin (brown means 11βHSD) . 11βHSD1 is expressed on the whole cells of epidermis while 11βHSD2 is expressed only on the outer layer. Obviously there is a regulated balance of 11βHSD1/2 in the normal conditions.
 (Keratinocytes synthesize and activate cortisol.Cirillo et al.J Cell Biochem. 2011 Jun;112(6):1499-505)

 The concentration of cortisol in the skin tissue is kept low basically and the constituent cells produce or inactivate cortisol according to the inflammatory status. Topical steroids application violates its harmony and constituent cells become instable after TS application. I consider it might be the essence of TSA existing as the ground of the barrier dysfunction caused by TS.
 
Sorry, the comment column is not available now. But the author believes readers can find some hints to overcome their own situations by the previous comments.

8 件のコメント:

  1. Hello Doctor.
    My name is Farah Rahim, I am the co founder of Natural Healing for Eczema (an online Facebook support group) in Malaysia.

    I think the theory can be backed up by this study
    Consequences of 11β-hydroxysteroid dehydrogenase deficiency during inflammatory responses

    http://www.era.lib.ed.ac.uk/handle/1842/4190

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  2. Thank you very much for your comment and I am sorry for my late response.
    I don’t know why but the comment space happened to close by mystake and the comment has not appeared for a while.
    I agree with you. Though it is only a hypothesis, we can feel relieved a little when the hypothesis succeeds in explaining the problem. Unexplainable phenomenon is really frightening especially for smart people like you.

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  3. Dr. Fukuya,

    Have you seen patients have flares in later stages after a long pause? There are some forum vets of tsw that have 4 to 6 months or even longer pauses from the withdrawal and then suddenly flare again in localized areas with oozing, red skin and symptoms like the beginning but not quite as debilitating. This upsets them a lot and we don't understand what causes this as no one has heard of a flare so late in the withdrawal. One member is 4 years into it and now has erupted again with oozing on the neck, behind the ears and very wrinkled skin again and on the legs which never flared before and seemed to be healed for a long time. Could it be the blood vessels remember some type of cycle and adrenals are not up to par? It happens to those who don't use any moisturizer for months as well so we know that is not the cause. Did you once say that it could take 10-30 per cent time to fully recover?

    Do you think the endocrine system needs to be monitored closer as well? Thanks for your expertise and time.

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  4. Please refer to my video (especially 5:58 and after it). It was a common experience for me.
    http://www.youtube.com/watch?v=mJ0IKTSse2E
    As for endocrine system, it has recently revealed that the skin itself produces cortisol. Skin and brain are two organs which produce cortisol by themselves other than adrenal gland. So there is a possibility that the skin has not recovered in cortisol production while adrenal gland is intact. But it is only a hypothesis at present.

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  5. Thank you, there is so much mystery with the withdrawal and I hope someday there will be something to ease this process.

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  6. Hi Dr Fukaya

    Not sure if my earlier post went through.
    If I understood this post correctly, it is saying that the application of TS causes an imbalance of 11βHSD1/2. The 11βHSD2 is increased to remove the applied TS while the 11βHSD1 is reduced since there is less need for natural steroid. The TSW effects is due to the lack of natural steroids once TS is stopped.

    Cross reference to your other post on 28th May 2014 on the effects of your hyaluronan lotion which states that the 11βHSD1 decreased and 11βHSD2 increased. Does this mean applying the lotion during TSW will aggravate the skin condition? Will you recommend to apply the lotion during TSW?
    I also bought the clofibrate, should I apply the clofibrate? The lotion and clofibrate are for my daughter

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    1. You are smart. I was also afraid of the same thing. I thought my hyaluronan lotion could help patients who were using steroids by reducing skin atrophy but I couldn’t expect the result in patients after TSW. I also thought my lotion could disturb production of natural steroids in TSW patients as same as you are thinking now.
      But through earlier questioners to steroid-users and non-users in Japan, I found my lotion seems to be effective in both patient groups. One example from overseas user is in the following URL.
      http://drfukaya.ocnk.net/page/11
      I can’t explain the mechanism. But in the above-referred overseas case, the skin before application of my lotion is obviously atrophic though the patient was in TSW. In such cases, my lotion seems to work well by thickening the skin.
      I can say that epidermis thickness (proliferation) is not regulated only by steroids. The fact that medium-sized hyaluronan increases the proliferation of epidermis is absolutely true but HSD1/2 balance is only one hypothesis or a part of the whole mechanism.
      So I recommend your daughter try to use both my lotion and clofibrate ointment. Because I think it is possible that one or both could help the skin condition improve.

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