Transcription
It's Medicos Perfectionist, once again resuming our discussion about bleeding and coagulation disorders. In the previous video, we have talked about hereditary angioedema. Today, I'm gonna teach you how to diagnose and treat hereditary angioedema. Now, let's get started. [Music]
First of all, the intrinsic coagulation pathways: high-molecular-weight kininogen activates factor 12 and 11. Prekallikrein only activates factor 12. High-molecular-weight kininogen being converted into bradykinin thanks to plasma kallikrein. Plasma kallikrein also activates factor 12 into factor 12a, which returns the favor by converting prekallikrein into kallikrein, which returns the favor by activating 12 into 12a, which returns the favor by activating prekallikrein into kallikrein. A positive feedback loop. What happens when you convert high-molecular-weight kininogen into bradykinin? Ah, bad things. Okay, pro-inflammatory things: contraction of non-vascular smooth muscle such as your bronchioles, increased vascular permeability, angioedema, and pus, increased vascular resistance, increased vasodilation, together lead to hypotension and increased pain. Chronic pain due to chronic inflammation. Now, the acute pain that you get when you hit your little toe into the sofa. High-molecular-weight kininogen into bradykinin things to kallikrein. That's why we call it the kallikrein-kinin system. There are two different types of kinin in the plasma: bradykinin and kallidin. If kallikrein is gonna stimulate the conversion of high-molecular-weight kininogen into bradykinin, kininase converting enzyme, on the other hand, is gonna block the stuff, and even if you have produced some bradykinin, it's gonna degrade it into inactive, ugly, useless metabolites. Bradykinin is taken to the cleaners by ACE. That's why we call ACE a kininase, because it gets rid of kinin. So, if angiotensin-converting enzyme is getting rid of bradykinin, what happens if you're taking angiotensin-converting enzyme inhibitors? There is no angiotensin-converting enzyme, so there is lots of bradykinin, because it's uninhibited and undegraded. If there is a word like this, so we have lots of bradykinin leading to all of this nasty stuff, including dry cough and angioedema, hypotension, etc. Also, the same angiotensin-converting enzyme used to convert angiotensin 1 to angiotensin 2, leading to all of the stuff. If you're taking ACE inhibitors, there is no hypertension, there is hypotension, and there is no increase; if, in fact, there are some troubles to the kidney, maybe decreased sodium reabsorption, increased potassium reabsorption leading to hyperkalemia, and increased hydrogen ion reabsorption leading to metabolic acidosis. And here are the side effects of ACE inhibitors: dry cough, angioedema, hypotension, renal impairment, metabolic acidosis, hyperkalemia. Na drug and pharmacology, just add nausea, vomiting, diarrhea as possible side effects. Why are you waiting for? I have 50 hematology cases on my Patreon. Go to patreon.com/slash medicos, become a patron. I'll give you my fifty hematology cases, guys, they are awesome. Go to patreon.com/scishow.
Let's talk about hereditary angioedema, because not all angioedema are created equal. We have the acute urticaria angioedema, such as allergy or hypersensitivity. Remember the mast cells and basophils and the IgE and stuff like that, crazy stuff like that, as well as immune complexes or serum sickness. By the way, what kind of hypersensitivity reaction is serum sickness? Is it one, two, three, or four? Let me know in the comments. Then we have the chronic angioedema, such as autoantibodies, aquagenic angioedema, aquagenic urticaria, as well as immune complexes. Then we have urticaria pigmentosa and systemic mastocytosis. If you remember mastocytosis, it was one of the myeloproliferative neoplasms. And we have complement-related and kinin-mediated angioedema, here being bradykinin, such as hereditary angioedema, which is the topic of today's video, acquired angioedema, which we're gonna discuss in a later video, ACE inhibitor-induced angioedema, because when you are using ACE inhibitor, there is less ACE and there is more bradykinin. Got it? As well as renin inhibitor-induced angioedema, because now all of the ACE is busy converting high-molecular-weight kininogen into the ugly bradykinin, because we don't need ACE to convert angiotensin one into angiotensin two since renin is history. Got it?
In the previous video, I've told you that hereditary angioedema is an autosomal dominant disease. Under normal circumstances, you have the C1 esterase inhibitor inhibiting kallikrein. When you have no kallikrein, you have no bradykinin, which is kind of okay. But in hereditary angioedema, you don't have the C1 esterase inhibitor or C1 inhibitor. Now, kallikrein is left free to crazy-but stuff, and bradykinin is increased from high-molecular-weight kininogen. And now bradykinin, the big pro-inflammatory babe, is on. So hereditary angioedema is an autosomal dominant disorder. Yes, decreased C1 esterase inhibitor, yep, increased kallikrein, and increased bradykinin leading to all of this nasty stuff. Don't forget the angioedema. We have three types of hereditary angioedema, not to be confused with acquired angioedema; they are two different things. Hereditary angioedema has three different subtypes. What are the functions of the C1 inhibitor, of course, C1 esterase inhibitor? First, it inactivates kallikrein, which produces bradykinin from the high-molecular-weight kininogen. When you inactivate kallikrein, you're not gonna have bradykinin, and that's normal. However, in hereditary angioedema, unfortunately, you don't have the C1 inhibitor; you will have kallikrein, and you will have bradykinin, causing symptoms. Functions of the normal C1 inhibitor: inactivate C1 esterase enzyme, oh yeah, it's called C1 esterase inhibitor, which cleaves C2 and C4 complement proteins in the classical complement pathway, which I'm gonna discuss soon. Third, inhibits factor 12 in the intrinsic pathway. The complement system: why did we call it complement? Because it complements the ability of antibodies and phagocytic cells to do their job. In brief, it complements the innate system. Cool. What does the antibody do? Fights inflammation, infection, kind of in a very simple way. Okay, we have three different types or pathways in complement. The difference is who will start the cascade, who will pull the trigger. What's the result? The results of either one of those or like any one of these pathways is the destruction of the organism. Cool, mission accomplished. Three pathways: the classical pathway, alternative pathway, and the lectin pathway. Who pulls the trigger in the classical pathway? The antigen-antibody complex. Classical complement pathway. What is the goal? To destroy the freaking bacteria. Who starts the cascade and pulls the trigger? Antigen-antibody complex. Cool, let's start. We'll convert C1 into the active form of C1. This dash means active. The enzyme is called C1 esterase. Oh, okay. Then C1's gonna convert C4 and C2 into active C4b, C2a and C4a. Got you. Then we have the C3 convertase. C3 convertase is gonna convert C3 into C3a and C3b. C3b is gonna combine with C3 convertase to form the C5 convertase. If it's called C5 convertase, I bet you it's gonna convert the C5 into C5a + C5b. C5b is gonna combine with C6, 7, 8, 9. This is the terminal complement system or the terminal complement, leading to formation of the MAC. The MAC is all of these stuff combined: membrane attack complex. Let's attack this bacteria, go to hell. That's the complement pathway. When you have C1 esterase inhibitor, it's gonna inhibit the C1 esterase. The complement is not gonna be activated. However, when you have a disease called hereditary angioedema, you don't have the inhibitor. The C1 esterase is left free to convert C1 into the active C1, C4 and C2 into the active stuff, and the complement pathways activated, baby, it's on. This is inflammation, this is an activated complement. The real problem in hereditary angioedema is that there is no bacteria; the body is just attacking itself, which is kind of weird. That's the definition of disease. So hereditary angioedema: you don't have the C1 esterase inhibitor. C1 esterase is left free, converting C1, C1 active, converting the stuff into this stuff and activating the complement. So hereditary angioedema is an ultra-complement-related, kinin-mediated angioedema. Now you understand.
What are the signs and symptoms of hereditary angioedema? Don't forget there is a positive family history, not in all cases, but some of them, really kind of leading to increased vessel permeability, which will lead to angioedema. It comes in attacks and episodes. Angioedema is swelling in the face, neck, extremities, as well as the genitalia. Recurrent attacks of pain. Remember bradykinin: pain, pain due to inflammation in the abdomen. This confuses lots of doctors; they think it's pancreatitis, they think it's colitis. Some crazy surgeons are gonna operate; they're gonna cut you open, and they're not going going to find anything abnormal. Shame on them. The typical patient is probably a young guy and adolescent. Why adolescent? Because it's genetic; if it's a genetic problem, and it's gonna be more likely it's a young patient. History of unnecessary surgeries, recurrent episodes or attacks, the last one to three days. They resolve on their own in one to two days. Don't forget there is no urticaria, meaning there is no rash in this disease. No pitting angioedema. Angioedema is a non-pitting edema because it's an exudate, not a transudate, and there is no itching. There are some triggers to the symptoms of hereditary angioedema. Those triggers include, first and foremost, dental procedures. The trauma, not the local anesthetic, the trauma is gonna trigger the symptoms in this poor patient, as well as stress, infection, surgery, accidents, menstruation, as well as alcohol. They trigger the symptoms. Between the triggers and the symptoms, sometimes, not always, there is a prodrome. The prodrome is just pre-symptoms of tingling, erythema, and nausea. So, for example, this young guy, like a 16-year-old person, went to his dentist, his dentist for a dental, then suddenly he started feeling tingling around his lips. Then, after this prodrome, starting the symptoms: swelling of the lips, swelling of the neck, swelling of the eyelids, swelling of the extremity, swelling of the genitalia, abdominal pain, etc., etc., etc. The edema can be disfiguring, which is really ugly.
How to diagnose hereditary angioedema? First, family history plus clinical. We have the history of triggers, prodrome maybe, and symptoms. Remember, no urticaria, no itching, and no pitting. Then let's go to the lab. The serum tests: how about the C1 protein of the complement? It's normal, indeed. It has increased function. All we have is converting C1 into active C1. So C1 is normal. C1q is also normal. C1q is part of the classical complement. Then we have C2 and C4. C2 and C4 are consumed, why? Because they are being converted into I don't know, like C4b and C whatever, but they are converted into something which will decrease their amount because all of them have become the active form. Cool. How about C1 inhibitor? If it's type 1, you have a genetic deficiency of the C1 esterase inhibitor. If it's type 2, you have a normal amount but decreased function. How do you test the decreased function of this crazy complement? Use something called a catalytic inhibition assay. How about bradykinin? It's high, baby. It's high. Prekallikrein is low, why? Because all of the prekallikrein has been converted into plasma kallikrein. How about the high-molecular-weight kininogen? And it's low, why? Because all of the high-molecular-weight kininogen has been converted into bradykinin. How about IgE? And it's normal. They are normal. This is not an allergic reaction due to hypersensitivity and crazy-but stuff like this. This is just bradykinin going mad. In type 3 hereditary angioedema, you have normal complement levels, remember, and normal C1 inhibitor, but you have overactivation of the crazy-but factor 12. Now you tell me where you can find this information organized in this beautiful manner. Like Wikipedia, maybe? Kaplan medical? I doubt it. Only with Medicos Perfectionist, you find this. Medical perfection.
How to treat this ugly disease? By the way, hereditary angioedema does not respond to antihistamines, steroids, or epinephrine, why? Because this is not an allergy, this is not a hypersensitivity. This is different from allergic angioedema, and remember we didn't have urticaria or itching, which proves it's not allergic. Cold. So ACE inhibitors are contraindicated, why? Because you remember ACE hates bradykinin. When you use ACE inhibitors, you will have lots of bradykinin because there is no bradykinin degradation. Lots of bradykinin, baby, it's on. To treat the actual disease, we have during the acute attack, and we have prevention of attacks. So the abortive therapy: C1 inhibitor protein infusion. If the patient is deficient in this crazy protein, give them the protein. Cool. Icatibant, which is a bradykinin receptor blocker. If all of the symptoms we're having are due to this crazy bradykinin, let's give a bradykinin receptor blocker. There's another drug called ecallantide, which is a kallikrein inhibitor. Remember kallikrein converts high-molecular-weight kininogen into bradykinin. So if you inhibit the kallikrein, you're doing great. If all of these are not available, you can use racemic epinephrine, why? To secure the airway. We usually give it like through inhalation as well as intramuscular. If all of the above is not available, try fresh frozen plasma. Why would you try fresh frozen plasma? Okay, fresh frozen plasma is normal plasma; it has all of the proteins that are contained in the plasma, including the missing C1 inhibitor. So if the patient is missing C1 inhibitor, you can give them fresh frozen plasma that contains the missing C1 inhibitor, but it's not recommended during acute attacks. If you know the answer to this question, you're brilliant. Let me know the answers in the comments. And of course, if none of these are available and you have a patient at risk of asphyxiation and blockage of the upper airway, of course, intubate: nasotracheal intubation. Remember your ABCs: first airway, breathing, circulation before anything else. Prevention of future attacks also has prophylactic therapy. We have danazol, which is an attenuated androgen. Again, you can give the C1 inhibitor protein, and you can use fresh frozen plasma. Fresh frozen plasma is actually very good for prophylaxis but not so good during the acute attack.
Here are some questions for you: number one, what's the most reliable and cost-effective screening test for hereditary angioedema? Number two, what distinguishes hereditary angioedema from allergic reactions? Why is fresh frozen plasma not recommended during the acute attack? The answers to these questions are available on patreon.com/medicos, and of course, let me know the answers in the comments. Next, we're going to talk about a crazy mnemonic about hereditary angioedema. Hey guys, if these videos are helpful, please, please consider supporting this channel on Patreon so that I can upload more than 10 videos every week. Yes, I can do it. Don't forget to subscribe, follow us on Facebook and Instagram, and support the channel on Patreon. You'll get all of my notes that I'm drawing, all of my nice illustrations, as well as 50 hematology cases. So go to patreon.com/crashcourse. Until next time, be safe, stay happy, and study hard. This is Medicos Perfectionist, where medicine makes perfect sense.