Dioxine et peau (MADISH) (Pour les professionnels)

Dioxin And The Skin (MADISH) (For Professionals)

• Case study of a human intoxication by 2-5mg of dioxine: effect seen in 3 months, study between 2004 and 2009

1. Dioxin stands for 2,3,7 8  tetrachlorodibenzodioxin-TCDD)

• Differential Diagnosis
  

1. chloracne is an inappropriate term (chloride is not implicated and it is not clinically or histopathologically acne).
2. Introduction of a new term: MADISH: Métabolizing Acquired Dioxin Induced Skin Hamartoma
3. Dioxin links itself to an intranuclear receptor (like a hormone): aryl hydrocarbon receptor (AHR), it is therefore lipophilic.

• Dioxin:

1. concentrates in the fat and remains there for a long time (chicken…)
2. Cannot be metabolized by cytochrome p450 in the liver
3. has a half life of 7-10 years
4. gene modulation is through cyp1a1, p27, bax…which influence: inflammation; proliferation; différentiation; métabolism…)
5. These different mechanisms affect the following organs: liver, pancreass, skin, joints, nerves, intestines.
6. *Dioxin is a xenobiotic. Others generally speaking such as cigarette smoke,  Amineptine (Survector, Servier) and tianeptine (Stablon, Servier) have been shown to induce similar lesions clinically.

• Our knowledge before this case of human intoxication:

1. available meta-analyses: none
2. identical cases: only one case report from Vienna in 1997 (girl intoxicated progressively whereas the following case was an acute intoxication). A second case report was also done in Vienna.
3. Seveso: accident in a Roche factory. The affected individual received twice the doses of those arroud the factory (1982)(this represent 20000 times the normal limit dose): clinically depressed scars were observed 15 years after the accident.

• Questions: what are the activated genes?: prospective genome-wide transcriptional responses and anaylses in blood and skin. on a total of 51980 genes (microarray):

1. 474 genes were modulated in the skin
2. 3928 genes were modulated in the blood
3. 79 genes were modulated in both the skin and the blood

• Histopathology:

1. what is abnormal in the skin of this patient:

-no sebaceous glands

-epidermal cysts: increase in ki-67 staining and pseudopodes as well as synthesis of new cysts

-deposit of mucin

-what is observed is that sebaceous glands are transformed into the hamartomas of MADISH

-action on the stem cells of the sebaceous glands sebaceous gland stem cell (SGSC)

-seebaceous glands affected, hairs and epidermis unaffected

-the activation of the promoter of CYP1A1 (Cytochrome P450) in transgenic mice induces expression of GFP (green fluorescent protein) in the liver, muzzle and the ears (JID 2008).

• Why then can we develop MADISH ? (physiopathology):

1. expression of the gene CYP, of the protein and kinetics of dioxin in the lesion:  Messenger RNA of  CP1A1 et CYP1A2 is massively expressed. This has also been put into evidence by immunohistochemistry. CYP is even more concentrated in new lesions and buds of new lesions.
2. metabolism of dioxin: the skin accumulates dioxin over 10-15 months and eliminates itself then as serum and lipids over 45 months. The concentration in the fat still remains 3 times higher than normal levels.
3. dioxin elimination is not only through metabolism but also through the skin who has a metabolism and metabolic effect twice that of fat.

• Treatment

1. No improvement was seen the first year following intoxication
2. Improvement was observed between May and November 2006 (the patient was officially diagnosed with the condition beginning of 2004 and officially declared cured in 2009)
3. dermabrasion was useful and excision of the cysts was done one after the other.
4. retinoids are a mistake in the treatment, steroids are moderately active

• What to do for the next patients ?

1. Admit that ancient cases were in fact MADISH
2. certain cases of Hidradenitis Suppurativa could in fact be dioxin intoxication.
3. Should biopsies be done in patients with acne?
4. AHR links itself to TH17, which in turn stumulates Il17 and Il22 (which induces epidermal proliferation). Would the new anti Il-22 be useful?

Source of information: “HMDP visiting expert” Professor JH Saurat -Singapore – january 2010

*Rencontres Romandes de Dermatologie et Vénéréologie – Morges, Switzerland – mars 2011