Porphyria: Pathophysiology

00:02 Welcome. In this talk, we're going to discuss yet another cause for blistering diseases. And this is porphyria.

00:10 It's actually porphyrias because there are multiple pathways, multiple enzymatic defects that will give rise to many of the same manifestations.

00:22 So it's multiple diseases, although there are going to be two major ones that we need to be concerned about.

00:28 So amongst the porphyrias this is a group of rare metabolic disorders.

00:34 What happens is that we have an enzymatic deficiency in the heme biosynthetic pathway.

00:40 So we're not making heme efficiently.

00:42 And that means that precursors in the long and detailed heme biosynthetic pathway are accumulating. It's those accumulated precursors that cause the pathology.

00:55 So the epidemiology of this, as I've already said, it's pretty rare. Although five cases per 100,000 population may seem a little bit high. It's mostly in the Americas, North America, as well as the European population.

01:11 Overall, considered to be rare disorders and individually, each genetic form is pretty rare.

01:17 The most common type I'm going to emphasize two types, but the most common is porphyria cutanea tarda PCT.

01:24 This has an interesting story.

01:26 Also, you may or may not have learned somewhere along the line in history about King George the Third, who was responsible for losing the Americas or North America from England.

01:39 And he drove them away with his taxation policies and everything else.

01:43 And it was thought that he was mad.

01:45 He did some pretty crazy things in terms of his governance of the British islands, but also of North America.

01:54 And it has long been suggested by historians that he had acute intermittent porphyria, not porphyria cutanea tarda, but the second most common form of acute intermittent. He had a history of skin rash.

02:08 He had muscular weakness.

02:09 He didn't have very good vision.

02:12 And his again going along with kind of muscle weakness, he had kind of an overall hoarse voice.

02:18 He had obstructive jaundice.

02:19 He also had frequent history of abdominal pains and he had very discolored urine.

02:24 All of these things sound like a porphyria.

02:30 But more recent evaluation has suggested that probably wasn't the case.

02:35 And he just had misdiagnosed bipolar disorder.

02:38 But if you remember all the symptoms that King George had, then you'll understand the symptoms that go on with porphyria.

02:46 The pathophysiology of this.

02:47 So again there are kind of eight steps in the biosynthetic pathway making heme from beginning to end. Seven of those are associated with various forms of porphyria.

03:01 And there are variable genetic patterns depending on kind of workaround pathways that the metabolic system can kind of put into place.

03:12 So there's a trigger we can actually drive this as we'll see by certain exogenous exposures in the appropriate genetic setting.

03:21 Hold that thought. And in any event it's mostly a single genetic mutation.

03:26 The heme biosynthetic pathway is disrupted.

03:29 So you start with delta aminolevulinic acid.

03:33 And that goes through a synthetase.

03:35 It goes through other deaminase and it goes through decarboxylase etc.

03:40 to finally make heme. If any of those steps are perturbed, you end up accumulating stuff that's upstream.

03:49 And those that accumulation of those precursors are toxic.

03:56 They are transported throughout the bloodstream.

04:00 They are incorporated into, say, red blood cells transported throughout the bloodstream, and then they get to the skin where their UV light with these ring structures will cause cellular damage.

04:16 We make oxygen free radicals.

04:17 We make a variety of reactive oxygen species.

04:21 And so there's a lot of photosensitivity.

04:23 So it's not just the genetic mutation it's UV exposure.

04:27 So hold that thought. The injury to the epithelium in the skin will give rise to blistering. And eventually if you have a lot of damage you'll get scarring.

04:36 You'll get pigmentation changes because as a result of scarring there's bleeding and accumulation of hemosiderin.

04:42 But it turns out, too, that some of these products will drive epithelial proliferation and even melanocyte proliferation.

04:50 So you will make more pigment.

04:53 Other associated symptoms include abdominal pain, a neuropathy, and psychiatric symptoms.

04:58 So that's why the madness of King George was such a good story.

05:02 It's too bad it's probably not true.

05:05 Okay. So that's the basis for kind of the pathophysiology.

05:08 Let's talk about the genetics because that's kind of interesting too.

05:11 Mainly I'm going to refer to porphyria cutanea tarda or PCT because that's the most common form. As you can see on the diagram, it's about half way through the total biosynthetic pathway for generating heme.

05:24 That's eventually going to be incorporated into hemoglobin.

05:27 The enzymatic defect is a mutation in Uroporphyrinogen III decarboxylase.

05:36 And if you can say that three times really quickly, you're a better person than I am.

05:41 It can be inherited in an autosomal dominant fashion, but it can also be a spontaneous mutation and the defect in the enzyme in precursor cells that are making it can be acquired.

05:53 Acquired can be triggered by alcohol use.

05:58 So dysfunctional liver can in fact acquire mutations or defects in the enzymatic activity of this enzyme.

06:10 It may not be an out and out mutation, but it may be a less active version of the enzyme that, in the setting of hepatic dysfunction, mostly alcohol abuse with cirrhosis, hepatitis C, and sometimes exogenous estrogens will give you just enough diminished activity of the enzyme that you will get the disease.

06:34 Okay. So that's the most common cause of porphyria.

06:39 The second most common cause is the one we wanted to ascribe to King George the Third.

06:44 And that's acute intermittent porphyria.

06:46 And that's a porphobilinogen deaminase that's a little bit upstream of the one that we the enzyme we just talked about in porphyria cutanea tarda.

06:56 But the outcome is exactly pretty much the same.

07:00 So the most common porphyria, which is what we're going to emphasize here, gives a variety of symptoms.

07:07 There's chronic blistering.

07:09 This is due, in fact, to the accumulation of the precursor in the skin. And then again UV generation of reactive oxygen species.

07:19 Because of damage to the skin, there's going to be fragility and blistering.

07:23 As I already said, you tend to get a hyper proliferation of the epithelium and also the melanocytes due to the action of some of these oxygen-free precursors or reactive oxygen species. So you get hyperpigmentation, you will get skin thickening, you may even get excess hair growth.

07:42 Damage to the skin will give rise to scarring.

07:44 And interestingly, these patients also described kind of a funny pigmentation of their urine, particularly when it stands.

07:53 So these precursor heme molecules that accumulate are very prone to oxidation just with atmospheric oxygen and undergo a color change.

08:05 So the urine that may start out yellow if it sits for a while, will turn red brown. And obviously these patients have photosensitivity, UV light is what's going to drive the generation of the oxygen free radicals.

08:17 Acute intermittent porphyria, the one that we wanted to give to King George. Second most common.

08:23 The peak incidence tends to be later on in life, and I don't have a very good explanation for that, because you would think that they're making heme from the very, very beginning. And why they would only present after three decades is not clear.

08:38 Women are more commonly affected.

08:41 As I've already mentioned, porphyria.

08:42 Porphobilinogen deaminase is the causal enzymatic defect, but its synthesis can also be affected by a variety of things, including hormonal stimulus.

08:54 So in the appropriate hormonal milieu, you may not get as much of the enzymatic activity as in others.

09:00 Symptoms are quite similar.

09:02 You can have colicky abdominal pain.

09:04 You can have neurologic abnormalities, including Psychiatric manifestations, disorientation, and you can also get the same skin lesions that we saw with porphyria cutanea tarda.