Transcription
We have talked about hereditary angioedema before. Today it's a quick review, a quick summary of hereditary angioedema. This will be a very fast video. If you find something that you don't understand, please go to my previous videos. Go to MedicalisPerfection Ellis, and then my playlists; the flavors is called Bleeding and Coagulation. With that being said, now let's get started. [Music]
First, you know the intrinsic coagulation pathway. Here we have high-molecular-weight kininogen by Kelly Curran; it's converted into bradykinin. High-molecular-weight kininogen activates factor 12 and factor 11 of the intrinsic pathway. Kelly Curran only activates factor 12. Here's the same thing here: high-molecular-weight kininogen thanks to kallikrein, bradykinin, kallikrein, and also activates factor 12. Factor 12a activates prekallikrein, which activates factor 12, which activates kallikrein. This is called a positive feedback loop.
What happens when high-molecular-weight kininogen is converted into bradykinin? Thanks to plasmic kallikrein, you have contraction of nonvascular smooth muscles such as your bronchial bronchioles and your bronchi. Increased permeability into pus and angioedema. Increased pain due to inflammation. Increased vasodilation. Increased vasodilation will lead to hypotension. That's why we call this the kallikrein-kinin system. Kallikrein and kinin, the bradykinin and bradykinin will do all of this crazy stuff. Bradykinin in the plasma, kallikrein in the tissue, high-molecular-weight kininogen in the plasma, low-molecular-weight kininogen in the tissue. If kallikrein helps high-molecular-weight kininogen be converted into bradykinin, angiotensin-converting enzyme prevents this step. And even if it has successfully produced some bradykinin, it's going to take them to the cleaner, converting them into ugly, dirty, useless metabolites. That's why we call the ACE a kinda nice because it gets rid of the kinin.
ACE inhibitors are going to inhibit ACE, no kidding. ACE is involved in the formation or no formation of prekallikrein, and ACE is also involved in the conversion of angiotensin I into angiotensin II. When you're taking ACE inhibitors, there is no ACE. When there is no ACE, there is lots of bradykinin, leading to a dry cough due to bronchoconstriction, leading to angioedema due to increased vessel permeability, as well as hypotension. When you block the ACE here, you have no angiotensin II, and then you have no hypertension; in fact, you have hypotension. That's why ACE inhibitors are one of the greatest antihypertensive medications. You can have problems with the GFR if you are on ACE inhibitors. Aldosterone is not going to be there, leading to natriuresis, hyperkalemia, metabolic acidosis. We have talked about side effects of ACE inhibitors. Now, the side effects of angiotensin receptor blockers. Angiotensin receptor blockers just block the receptor, the AT1 receptor of angiotensin II, but they do not touch the ACE enzyme. So bradykinin is not going to be high. This is wrong, so I'm going to be high. Okay, so don't have symptoms of bradykinin. Okay, great. But you still have these symptoms: you still have hypotension, you still have notorious hyperkalemia, metabolic acidosis, some orthostatic hypotension, and dizziness, but you don't get dry cough and you do not get angioedema.
If you are a visual learner like myself, here is a great slide for bradykinin effects: bronchoconstriction, hypotension, and angioedema. See the swelling of the lips, swelling of the eyelids, and laryngeal edema or carrying angioedema classification. We have many different subtypes. There is the allergic or the hypersensitivity type of angioedema, but this is not what we're talking about when we're talking about hereditary angioedema. Hereditary angioedema is here; it's complement-related and kinin-mediated angioedema. It's not allergic; it's not a hypersensitivity reaction. Aquagenic urticaria is here. Do you remember aquagenic pruritus or aquagenic eating? Yes, indeed. This was the great polycythemia vera, one of the myeloproliferative neoplasms. Hereditary angioedema is an autosomal dominant disease. Translation: you have two copies of genes; one of them are mutant and the other one is normal on the pair of chromosomes. You have a 50/50 probability of passing the disease to your children, so 50% of them will be affected with hereditary angioedema; the other 50% will be normal. Hereditary angioedema is an autosomal dominant disorder where there is a deficiency of C1 esterase inhibitor, most of the time. Normally, the C1 esterase inhibitor inhibits kallikrein. When you inhibit kallikrein, you do not have bradykinin, which is good because bradykinin is pro-inflammatory, and under normal conditions, I don't need inflammation, so that's cool. However, in hereditary angioedema, you don't have the C1 esterase inhibitor. Kallikrein is left uninhibited; bradykinin is high in the sky, and this will lead to all of the crazy but stuff caused by bradykinin, such as dry cough, angioedema, hypotension, natriuresis, etc. Fifty hematology cases for a limited number of people are available on patreon.com/medicalis. Don't miss out.
Hereditary angioedema, genetic disorder, decreased C1 esterase inhibitor, increased kallikrein, increased bradykinin, some increased kallikrein, just it's not inhibited, increased bradykinin, two of the stuff: dry cough, hypotension, and angioedema, which is an emergency. My bradycardia mnemonic: everything here is B or P. Three types of hereditary angioedema: type 1, there is a deficiency of C1 inhibitor, decreased in number, so type 1, none. Type 2, the number is is kind of okay, but we have decreased function. So in type 2, C1 inhibitor is too weak. Type 3, Roman numerals 1, 2, and these are three digits. So in type 3, C1 inhibitor is normal in number and function; however, factor 12 has gone crazy.
Functions of C1 inhibitor: under normal condition, inactivates kallikrein, which produces bradykinin; we know that. Inactivates C1 esterase enzyme, which cleaves C2 and C4 components or proteins of the classical pathway complement. Okay, it inhibits factor 12a in the intrinsic pathway. The complement system; we call it complement because it complements the job of the antibody. We have three pathways: classical, alternative, and lectin. In hereditary angioedema, it's the classical pathway that's involved. Antigen-antibody complex will pull the trigger and store the complement cascade until we end with the MAC, the membrane attack complex, and the MAC will attack. Here's the classical pathway: antigen-antibody complex will pull the trigger, converting C1 into the active C1 thanks to C1 esterase. Then we have C4 and C2 into C4b2a and C4a. C3 convertase will convert C3 into C3a and C3b. C3b together with these three combo days will form C5 convertase, which will convert C5 into C5a and C5b. C5b together with C6, C7, C8, and C9 will form the MAC, which will attack. The problem in hereditary angioedema is that there is no bacteria; the body is literally attacking itself, which is weird. That's why it's a disease; it's a pathology. Pathology is the scientific study of people gone weird. In hereditary angioedema, you have a deficiency of the C1 esterase inhibitor. If you have a deficiency of the inhibitor, C1 esterase is left uninhibited, activating the complement, activating the complement, activate complement until you destroy yourself, metaphorically speaking. So when I don't have the inhibitor, I have C1 esterase overactivated, left uninhibited. C4 and C2 are consumed, and the MAC is overactivated. That's why we call it complement-related, kinin-mediated angioedema.
Clinically, hereditary angioedema has a positive family history, has increased bradykinin, increased vessel permeability, leading to recurrent attacks of angioedema, which is swelling in the face, neck, extremities, eyelid, lips, and laryngeal edema. Recurrent attack; the attack lasts between two to three days, okay, and then they resolve in one to two days, okay, but they may resolve, or you may die from asphyxia. Okay, we can't attack off abdominal pain because bradykinin pain, and you can have swelling in the genitalia as well. The patient is usually young, and because it's a genetic problem, no other carrier, no petting, no itching, because this is not an allergy. They're recurrent episodes, as you know, and the abdominal pain can mimic pancreatitis. Sometimes surgeons are fooled. In many instances, there is a trigger that triggers the symptoms of hereditary angioedema, and sometimes there is a prodrome between the trigger and the symptoms. These are the triggers; please don't forget dental procedures.
Diagnosis: you need the family history, and you need the clinical picture of triggers, prodromal symptoms, and the clinical features. Okay, now let's go to the lab. How about C1? C1 level is normal; C1 function is normal. C1 and C1q, okay. C2 and C4 are consumed. C1 inhibitor is low. That's the definition of hereditary angioedema. Bradykinin; that's what's causing the angioedema and all of the crazy symptoms. Prekallikrein is low because all of the prekallikrein has been converted into kallikrein. High-molecular-weight kininogen is low because all of the high-molecular-weight kininogen has been converted into bradykinin. IgEs and IgGs are normal because this is not an allergy; this is bradykinin; this is not histamine.
Have to treat this hereditary angioedema. This is not an allergy; don't give antihistamines, steroids, or epinephrine. It's bradykinin; it's not histamine. ACE inhibitors are contraindicated because they will increase bradykinin. During the acute attack, you should infuse the C1 inhibitor. You can use Icatibant, which is a bradykinin receptor blocker, or Ecallantide, which is a kallikrein inhibitor. Okay. Prevention of future attacks: Danazol, C1 inhibitor infusion, and fresh frozen plasma. Fresh frozen plasma is better used in the prophylaxis than rather than the acute attacks; it's not that good. What if I have a patient during the acute attack and I don't have all of this stuff because I'm in a very poor hospital? Give FFP, give racemic epinephrine. I don't have any of this? Intubate. So here's a mnemonic for the treatment during acute attack: I can tab. And I can tab. And I'm a bradykinin receptor blocker. Ban bradykinin. Bradykinin receptor antagonist. For Ecallantide, it's a kallikrein inhibitor. And here is everything you need to know about hereditary angioedema in just one slide, which is awesome. Thomas Edison said, "Genius is 1% inspiration and 99% perspiration." Another mnemonic for hereditary angioedema. Here are some questions for you. Let me know the answer in the comments, and the answers are available on Patreon in an amazing slide, just on Patreon. If this video has helped you, please support this channel on Patreon. I need your support, guys, please, so that I can upload more than 10 videos every week. Thank you, guys, for watching. Subscribe and hit the bell. Smash like. Follow me on Facebook, Instagram. Get all of my notes, all of my cases by going to patreon.com/medicalis. I'll send you my bloody Dropbox links. Thank you, guys. Be safe, stay happy, and study hard.