Ichthyosis Vulgaris: Pathophysiology

00:01 Welcome. In this next talk, we're going to cover an interesting pathology that kind of says what it looks like.

00:08 So this is ichthyosis vulgaris.

00:11 And you can just say it's IC.

00:12 Um we'll see why it's called ichthyosis.

00:15 That literally means fish like or fish scale like.

00:19 And the vulgaris is because someone along the way decided that it was vulgar.

00:24 In any event, it is a keratinization disorder.

00:27 The skin itself, the epithelium is reasonably normal.

00:32 But that keratin layer on top, the so-called dead skin that's now just cross-linked intermediate filaments, is too thick and it's too thick and in kind of an irregular way. So you have increased keratin layer with dry and scaly skin.

00:50 Let's talk about some of the epidemiology of this.

00:52 So it's not that uncommon.

00:55 Uh, in a class of medical students, roughly one out of 250 of you will have Of ichthyosis vulgaris and the vast majority of cases, although there is no sex predilection or ethnic predilection.

01:10 95% of the cases are hereditary, so they have a genetic basis.

01:14 There are 5% that don't, and we'll briefly talk about those.

01:18 So in terms of the pathophysiology, what's going on with the hereditary form, which again is 95% of cases there's a loss of function mutation in the Filaggrin gene.

01:29 And if you go back and look at the general talk we talked about normal structure and function of the skin. You will see that I talked about filaggrin as part of the stratum granulosum layer. It's an important protein that get expressed at that layer.

01:42 It's an autosomal dominant disease.

01:44 So that means that if your parents, one of your parents has it, 50% of the offspring will have it as well.

01:52 Although there is variable penetrance, there are other genes that can modulate the expression of Filaggrin or can affect the layering of the stratum stratum corneum, the very top layer. So the acquired cases this is a minority, but the required cases kind of fall in two categories.

02:10 One is due to malignancy.

02:12 And if a patient suddenly presents with ichthyosis vulgaris in their 50s or 60s, your first thought should be that they may have a tumor someplace.

02:22 Then there are also systemic diseases.

02:24 These include acquired immunodeficiency syndrome, systemic lupus erythematosus, or celiac disease for amongst others, and celiac is also known as gluten sensitive enteropathy.

02:37 So what's going on here? Here's our kind of going to be our schematic of skin.

02:42 And there's a basal layer that is the germination layer.

02:46 That's where the new keratinocytes are going to be born and that is there.

02:51 Above that are going to be varying layers of progressively maturing stratified squamous epithelium. So that is the stratum spinosum layer.

03:01 And then on top of that is going to be the granular layer or the stratum granulosum.

03:06 And in there, the keratinocytes in that layer are going to be producing those filaggrin granules. And filaggrin is a structural protein that is going to be very important for directing the final terminal differentiation of the keratinocytes, changing them from viable cells to non-viable with cross-linked keratin over the surface.

03:25 And also is going to be very important for cross-linking and making a mature stratum corneum layer the very top air barrier layer.

03:36 So the filaggrin breaks down into a variety of water retaining.

03:41 So they're called hygroscopic amino acids.

03:43 And they include histidine, urocanic acid and pyrrolidone a carboxylic acid. And all of those will moisturize the skin and protect against UV damage, but they also part and parcel of the breakdown the catabolism.

03:58 Filaggrin also involves generating peptides that will help cross-link the keratin.

04:06 So that's our normal structure now represented on the left.

04:09 Let's see what happens. If you happen to have ichthyosis vulgaris your basal layer looks fine. Your stratum spinosum looks awesome.

04:19 Now the granular layer, the stratum granulosum is a little bit thinned. And you're not making as much of that important protein, the filaggrin. So you have diminished filaggrin granules.

04:29 As a consequence, you're not making the emollients. You're not making those hygroscopic amino acids.

04:35 And the cross-linking of the overlying keratin is abnormal.

04:41 In fact, you end up with a very thickened layer of the stratum corneum.

04:47 And we have more and more and more of this accumulating.

04:49 And that's the scale that you see grossly.

04:52 So that's why it has that particular appearance.

04:56 So remember an acquired ichthyosis in malignancy.

05:00 This would be a paraneoplastic process and is associated with the production of a variety of proteins that can occur in some hematogenous malignancies, such as Hodgkin's disease or some other leukemias or lymphomas.

05:15 Autoimmune disease. There is immune dysregulation, and as a result of that, cytokines that will affect the granulation of the stratum granulosum and the production of the filaggrin.

05:27 You can also have hypermetabolic states or hypermetabolic states that influence the production of filaggrin.

05:35 So hypothyroidism or other disorders that reduce the metabolic rate of those cells can also give you acquired ichthyosis.

05:43 And then certain drugs a whole variety of drugs have been described that can give you those lesions. But again for your future kind of clinical training, if you see a patient who suddenly presents in their 50s or 60s or 70s with the scale that we're going to see in a second of ichthyosis vulgaris, I do suspect that there is a malignancy lurking someplace.