Transcription
Hey guys, it's Medicosis Perfectionalis, continuing our bleeding and coagulation disorder series. In the previous video, we talked about bradykinin and the kallikrein-kinin system, as well as high-molecular-weight kininogen. Today, let's talk about hereditary angioedema—swelling of the lips, of the face, of the eyelids, and even the genitalia. Yes, indeed, this is today's topic, and let's get started. [Music]
Here is your famous high-molecular-weight kininogen. Thanks to plasma kallikrein, we have bradykinin. High-molecular-weight kininogen activates factor XII, as well as factor XI. Plasma kallikrein only activates factor XII. This is the intrinsic pathway. So, high-molecular-weight kininogen is being converted into bradykinin. Plasma kallikrein also activates factor XII of the intrinsic coagulation pathway into the active form of factor XII. Then, the active form of factor XII returns the favor by converting prekallikrein back into kallikrein. Kallikrein is going to activate factor XII into XIIa, which is going to activate prekallikrein into kallikrein, and so on and so forth. This is called a positive feedback loop—very important.
High-molecular-weight kininogen, thanks to plasma kallikrein, produces bradykinin. Bradykinin contracts the nonvascular smooth muscles, such as your bronchi and bronchioles—dry cough. It increases vessel permeability—edema and angioedema. It increases pain. It increases ventilation and natriuresis, which means sodium loss in urine. Those will lead to hypotension. Bradykinin is a pro-inflammatory mediator, big time. It's very similar to histamine, but not the same. In the plasma, we have bradykinin and prekallikrein. In the tissue, we have kallidin and tissue kallikrein. If plasma kallikrein is going to stimulate the step from high-molecular-weight kininogen into bradykinin, angiotensin-converting enzyme is going to inhibit this. Even if you succeeded in producing bradykinin, it's going to convert it into inactive metabolites. This is called degradation. A takes bradykinin to the cleaners. We talked about the adverse effects of ACE inhibitors in the previous video. So, ACE inhibitors—now we don't have ACE, so now you have lots of bradykinin. Bradykinin will lead to all of this fun stuff: dry cough and angioedema, for example, or for instance. Also, ACE converts angiotensin I to angiotensin II. If you're taking ACE inhibitors, there is no ACE, so there is no angiotensin II. You will decrease your blood pressure. That's why ACE inhibitors are excellent antihypertensive medications. But, as side effects, you can damage the kidney; you can lead to natriuresis, hyperkalemia, as well as metabolic acidosis. Side effects of ACE inhibitors: dry cough and angioedema, hypotension and angioedema, renal impairment and natriuresis, acidosis, and hyperkalemia.
I've talked about the renin-angiotensin-aldosterone system in the previous video, but in brief: you have renin from the kidney converting angiotensinogen from the liver into angiotensin I; then ACE, angiotensin-converting enzyme from the lung or the endothelium, converting angiotensin I to angiotensin II. Angiotensin II is going to act on the receptor, leading to vasoconstriction of the arterioles, aldosterone releasing to increase sodium reabsorption, decreased potassium reabsorption, decreased hydrogen reabsorption. This is the same ACE that inhibits the production of bradykinin, as well as degrades it. And here is bradykinin, and a visual kind of illustration: bronchoconstriction, hypotension, and angioedema, and constriction of the airway, which can be an emergency.
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Now, today's topic: hereditary angioedema. So, let's nip it in the bud and kick it in the butt. Formerly known as angioneurotic edema, it's an autosomal dominant disease. Translation: it's a hereditary condition. More translation: the patient has two chromosomes; one of them carrying the mutant gene, and another chromosome, or the other pair carrying, or the other like part of the pair carrying the normal gene. So, if this is the abnormal gene, this is the normal gene. So, here, the big A is dominant; that's why it's an autosomal dominant disease. So, here is an example: a nice couple marrying each other. Here is an abnormal person; has the abnormal gene, big A, small a. Here's the normal person, small a, small a. Then the offspring, big A, small a, is affected, why? Because the big A is dominant; it's an autosomal dominant disease. Big A, small a, affected; small a, small a, not affected; small a, small a, not affected. So, 50% of the offspring are affected; they have the disease, and the other 50% is perfectly normal. So, what's the probability that this patient is going to pass down the disease through the next generation? It's 50/50.
So, hereditary angioedema: autosomal dominant disorder leading to decreased C1 esterase inhibitor—C1 inhibitor. So, normally, you have the C1 esterase inhibitor inhibiting the plasma kallikrein. Plasma kallikrein is used to produce bradykinin. Now, if there is C1 esterase inhibitor, like normal circumstances, it's going to inhibit kallikrein and stop the production of bradykinin, which is cool, because bradykinin is pro-inflammatory, and under normal conditions, we don't want inflammation—cool. So, C1 esterase inhibitor decreases bradykinin; this is normal condition. Next: pathology, please.
So, hereditary angioedema: we have decreased C1 esterase inhibitor. The kallikrein is left uninhibited, leading to a production of bradykinin. So, when you have deficiency of C1 esterase inhibitor, you have lots of bradykinin, which is pro-inflammatory, big time. It's going to lead to vasodilation, increased vessel permeability, pain, etc., etc. Don't forget dry cough and angioedema. So, hereditary angioedema: autosomal dominant disorder leading to deficiency of C1 esterase inhibitor. Kallikrein is left uninhibited, and there is lots of bradykinin, which will lead to all of this fun stuff that you know: hypotension, pain, increased vessel permeability, and angioedema, as well as bronchoconstriction and dry cough. Why? Because there is no C1 esterase inhibitor. Kallikrein is left uninhibited, leading to a production of bradykinin—very simple.
So, what are the symptoms in hereditary angioedema? He will have increased vessel permeability, edema, natriuresis, vasodilation leading to hypotension, bronchoconstriction leading to dry cough. Where is the pain? The abdomen is a classical example. Abdominal pain is very common. There are types of hereditary angioedema. Type 1: 85% of cases, the most common type. It's an autosomal dominant disease; we have deficiency of C1 inhibitor—decreased number. Type 2, on the other hand, again autosomal dominant: the function of C1 IH is not decreased number, but decreased function. It's not that the amount of the enzyme is decreased; it's the function. Type 3 is kind of weird: C1 inhibitor is perfectly normal; however, factor XII of the intrinsic coagulation pathway is crazy—is mutant, is abnormally activated, overactive—will lead to bradykinin. How come? Let me explain.
So, here is type 3: factor XII is overactive. This pathway is on fire, baby. When you have lots of activation here, they're going to activate prekallikrein into plasma kallikrein. Remember the positive feedback loop? Now, high-molecular-weight kininogen is being converted into bradykinin because kallikrein is on fire—cool. So, now, C1 inhibitor is perfectly normal; factor XII is overactivated; now kallikrein is active or increased in production, which will increase the production of bradykinin. That's how we get the symptoms of hereditary angioedema, even though C1 inhibitor is fine. Now let me ask you a question: in patients with hereditary angioedema, do you expect the level of prekallikrein to be increased, decreased, or normal? And the answer is decreased. Why? Because all of the prekallikrein is being converted into kallikrein—good. How about the high-molecular-weight kininogen level? Is it high, low, or normal? And the answer is it's low. Why? Because all of it has been converted into bradykinin, baby.
In the next video, we're going to talk about hereditary angioedema diagnosis and treatment—how to diagnose it and how to treat it—in the next video in our playlist about bleeding and coagulation disorders. That's why you need to subscribe. And if you want to get all of my notes that I'm drawing right now, all of these nice slides in my presentation, you can get them on patreon.com/medicosis. Plus, I'm going to give you 50 hematology cases. Go to patreon.com/medicosis; I'll send you my bloody Dropbox link. Thank you so much for watching, and as always, be safe, stay happy, and study hard. This is Medicosis Perfectionalis, where medicine makes perfect sense.