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Hyperlipidemia

by Carlo Raj, MD
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    00:01 Metabolic syndrome. Now, with hyperlipidemia, we are going to go into further detail because it is important for you to understand the biochemistry of well maybe, just maybe, it might be part of what is known as your hyperlipidemia with acquired meaning to say that you are trying to lose weight and you are eating too much or the fact that you might have genetic issues in which you have no control but you have to be careful. And so these are the things that you need to make sure that you explain to your patient so that they know as how to deal with their particular issue. So to begin at the top end here, I want you to understand as to what is going on in the schematic so that you can clearly see as to what is the normal pathophys and biochemistry of the lipid that we are going to consume from our mouth and it is making their way all way over to the liver. Here let us say that you just had a fatty meal. You just had a broad roast, you just had a burger from McDonalds. So that means that the fatty meal. So, now you just ate a fatty meal. For effective digestion as far as your licensing boards are concerned, what do you want to know? Sure you have a little bit of lipase in your mouth. I am not arguing that, but in terms of effective digestion of your fat would not be in the mouth. The effective digestion maybe perhaps in the stomach. Well, once again it is going to assist with fat digestion there as well. You have acids might then break apart your meat and such, if you are consuming them, but in terms of effective digestion of your lipid, it begins in the duodenum.

    01:40 Is that clear? Really. Remember if I ask you this question which is this patient has a right upper quadrant pain postprandial. Every time this patient has a meal, there is going to be right upper quadrant pain. What is happening with this patient? What is the name of the hormone and name of the cell that is responsible for causing this pain after eating a fatty meal? It is the fact that you are working upon your I-cells. And the I-cells are going to release what please? Your CCK. Could that be a question? Sure it can. It can be from physio, it can be from path. What does that mean to you? What is causing this right upper quadrant pain after eating a fatty meal? It is the fact that the I-cell releasing cholecystokinin works on a gallbladder, which is the pathology. Might be cholecystitis, isn't it? And gallbladder contains what? It contains bile. Why do you require that bile? Now we get into the effective lipid digestion. We had this bile, which is then being housed in your gallbladder, which makes its way to the second part of the duodenum. Are you there? Are you with me? Good. And do you see this enterocyte? And so therefore that bile coming into the second part of the duodenum is going to surround the triglycerides. And when you surround your triglyceride with bile, which is it called? You call this a micelle. You call this as a color micron. What do you call this? You call this as a micelle, don't you? So micelle has been formed with emulsification process. What is it going to do? It does exactly that it emulsifies the triglycerides because the triglyceride can, you can see those finger-like projections. Those finger-like projections are the brush border of your duodenum, shall we say. You see where's the free fatty acids in glycerol that would be the lumen of the duodenum. Are you with me? And this has now become emulsified with the help of bile. Then you are going to create this free fatty acids, FFA, which is then going to make its way through the brush border into the enterocyte, stop there for a second.

    03:47 Earlier with the question that I was trying to post you in terms of what was it that caused the pain postprandial? It is the fact that cholecystitis was then aggravated by the hormone, which is being released by the lipid, which was making its way down into duodenum. Clear? What was the cell that released CCK? It's called the I-cell, isn't it? The bile that is emulsified get back to normal here and continue through the biochemical process So we're now inside my enterocyte, we are going to now recreate the triglyceride. We are going to reesterify what is called? When you reesterify, think of this as being X-men. What does he do? It disintegrates. He goes through the wall and then he reappears. That is what this is doing. The triglyceride went through the wall. It first became free fatty acid or monothioglycerol and then it reformed into triglyceride. Here I am. What are you going to do with me? You are going to form a chylomicron nascent. What does nascent mean? Baby, neonatal. It is nascent chylomicron. What kind of apolipoprotein do you require? You must memorize apo B-48.

    04:58 It is imperative that you know that. The apo B-48 has now formed a chylomicron. What does a chylomicron have in it? It has triglycerides. What we are trying to get to? What is your objective for this entire illustration? It is a fact that you have lipid that you're consuming from your mouth making its way to the liver. Is that clear? So now you have a chylomicron.

    05:21 What is the number 1 method, what is the preferred method of transport of every lipid? It is through your lymphatics. You see lymphatics. So there it is. If you are doc like I am, then you will notice that after you eat and if you were to do ultrasound, you can actually see after a lipid-rich meal, a river of chylomicrons running through your lymphatics absolutely magnificent. You find these lymphatics that is going to make its way eventually where? Into thoracic duct, empty into right atrium. Are you there? Good. And from the right atrium, where are you going to enter? You are going of course enter your blood vessels. This is important, isn't it? Inside the blood vessel, there are couple of things that I wish to bring to your attention. Here you will notice that HDL.

    06:06 What does HDL mean to you? It is called "good cholesterol", isn't it? So that "good cholesterol" is then going to donate its C-II and E to the nascent chylomicron. What nascent means? Neonatal, baby. Think of in that way. You have been united. What does that mean? HDL comes over to chylomicron and says "Son, you have now been united. I am now importing onto you C-II and E." And now you have a mature chylomicron, still filled with what please? Triglycerides. Where are you? In your blood vessel. Literally in your circulation.

    06:48 So now then we have matured chylomicrons what is the objective? To make its way to the liver.

    06:53 Let us continue. Alright now, here's number 2. Number 2 says CPL, that means capillary lipoprotein lipase. CPL is capillary lipoprotein lipase. Eventually, what you are going to do here? We are going to plug in this pathology. But if we don't understand the normal first, it makes it quite impossible for you to understand what is going on with the pathology. You're just memorizing and it won't be in your best interest. So the capillary lipoprotein lipase, you pay attention to lipase is then going to take the triglyceride from your chylomicron and extract it. Is that clear? And the triglycerides what is known as your fat muscle. But now what do you know? You have an empty chylomicron. You see the chylomicron number 3. It is empty. It has emptiness syndrome. "Oh! my baby has left me." What do you mean? The triglyceride has been removed, by whom? Capillary lipoprotein lipase. This is the second lipase actually from biochemistry they come into play second. Second. Who is the first one? In biochemistry way back versus free fatty acids. Those need lumen of the duodenum. You had your first lipase. You did, you see it in biochemistry you referred to or you learned about pancreatic lipase. Keep that separate from what we are looking at here in pathology, which is capillary lipoprotein lipase, CPL. Is that clear? Make sure that you understand this well. Repeat me if you need to so that you are clear about which lipase deals with what. There is the third lipase, which you learned about in biochemistry. The third lipase only comes into play after the fat has been stored. And so that it is referred to what's known as hormone-sensitive lipase and that is something that you and I will be looking at in endocrinology. Let us continue. So now that we have an empty chylomicron, what you need so that you can be taken up by the liver? It is called an E-receptor. You take a look at that 3. So number 3 is dealing with what is known as the E-receptor. Now let us take number 1, let us take number 2, let us take number 3. And now that you have understand the flow of this illustration, you can see how clearly you can understand what is going on with your patient and the presentation.

    09:04 The first one, number 1 is abetalipoproteinemia in which you literally are not able to form a proper chylomicron because apolipoprotein B or apo B-48 is not present, pathology number 1.

    09:17 Pathology number 2, it is the fact that you need to have C-II. Where does the C-II come from? I know that we speak in different language, but you and I right now, we are seeing eye-to-eye only. We have to and we have to speak the same language and that is where I am trying to get you right now. So you need C-II, pay attention. That C-II is there to stimulate your CPL. What CPL stand for? Capillary not pancreatic and it is definitely not hormone sensitive. Is that clear? The capillary lipoprotein lipase. If that C-II exists to stimulate that CPL. What if there's deficient of C-II? The lipoprotein lipase isn’t working.

    09:57 If that is not working, oh! my goodness, we are accumulating in your patient, tons of chylomicron. What does chylomicron mean to you in terms of presentation of your patient? Is that triglycerides or cholesterol? Good. Triglycerides. So your patient is going to have triglyceride levels, it will be ridiculously elevated. Even 150 is high, 300 is really high, 1000s is what I am talking about, triglyceride, not a good thing. Is that clear? That is pathology number 2. Pathology number 3, I would like for you to take that E-receptor and you see the horizontal line. How many horizontal lines you see with that E? One, two, three good. So there are three lines. Therefore, type III. We talk about this coming up on a table, not to worry, all I am doing here is introducing concepts here and pluging in relevant pathologies. So type III, what's known as hyperlipoproteinemia, is actually missing your E-receptor. So guess what, you cannot properly take up your chylomicron remnant into your liver. It is called remnant removal disease but another name that you want to know for this is called familial dysbetalipoproteinemia.

    11:13 Here were go. Pathology 1, 2, and 3, spend a little bit of time here everything that you need to know about these pathologies begins with understanding the biochem, the phys and then eventually the disease processes. Now if that was from the mouth to the liver, what are we going to do next? We are going to take this lipid and we are going to then deliver to the tissues. What tissues? May I ask you something? Could you picture adrenal cortex, close your eyes. Adrenal cortex, what are the layers? G, F, and R. What are they? Glomerulosa, fasciculata, reticularis, interesting. Tell me about the fasciculata. What is producing fasciculata? I do believe it is called cortisol. Good. If it is cortisol that you are producing, how in the world do you even begin the synthesis of your aldosterone, glomerulosa.

    12:01 Cortisol, fasciculata. Sex steroids, reticularis. Fasciculata, reticularis and glomerulosa on the superficial side. How do you even begin the process of synthesizing those hormones? It begins with the process of cholesterol being cholesterol, meaning properly delivered to the tissue, not triglycerides. What is cholesterol like to live? What kind of package does cholesterol like to be in? It likes to be in LDL. Are you clear about the target? What you have here in your tissue is going to, we see what number 1 is. That number 1 represents LDL receptors. Those LDL receptors represent what target tissue that you are referring to? Target tissue as an example that I just gave you was your adrenal cortex. Now before we get to that, take a look at the liver.

    12:51 From the liver, we are going to then deliver, triglycerdies at first into circulation. We are going to go through a number of processes in which that triglycerides then becomes your cholesterol that is being properly delivered to the tissue. Let us begin. From the liver is where we are and just like we began in the previous discussion where we looked at your chylomicron, where do they come from? The enterocyte right? What did you require for formation of your chylomicron? It was apo B-48. Good. Here the triglyceride is being delivered by TC versus VLDL. That VLDL is what is going to then transport your triglyceride. TC versus apo B-100 how important is that? Ridiculously important. Apo B-100 is a component that is required for proper VLDL formation. What does it contain? Triglycerides.

    13:49 This is, at first, a precursor, a nascent VLDL. It is young. It is a baby. What was it that then matured chylomicron? Son, you have been united. Who united that particular baby vessel or package? It was called HDL. You have it here again. TC versus HDL. HDL is going to then also implant or deliver C-II and E here as well to VLDL to form a proper immature VLDL. In the meantime, you will see an exchange of what's known as CETP, all that is part of biochemistry that we do not have time to go through, but it is important that you understand the proper exchange between VLDL and HDL. Where am I now? Your inner circulation. Where do VLDL come from? It came from the liver. Keep this separate please from your chylomicron that we discussed earlier. In the meantime, what you also find from the intestine it is important for you in biochemistry as well is some of your long chain fatty acids, your LCAT.

    14:50 So all of this is then going to allow you to properly form your HDL. And what you know about HDL? HDL is a scavenger. Scavenger of what? It is a scavenger of cholesterol. What do we call HDL? We call HDL good cholesterol. What is the magic number that you want to know for HDL? It is called 50. Remember that. Why? Because if your patient has an HDL less than 50, not a good thing. So you want HDL to be on the higher side because it will scavenge the cholesterol specifically in the blood vessels and such. Let's continue. Now that we have VLDL what does it contain? Triglycerides. So I will ask you this question. What does the tissue require for proper synthesis of your cell membrane if a tissue required let us say production of your cortisol or if it's done in your gonads, you needed to produce what? Testosterone, estrogen. It was not triglycerides that you were delivering. It is the fact that you are delivering your cholesterol. What are you going to do now? Quickly we are going to go through intermediates. So there are not enough capillary lipoprotein lipase, CPL. You taking the triglyceride and you are forming IDL. What does IDL mean to you? Intermediate density lipoprotein. And this IDL eventually is going to form your LDL right now for pathology purposes, we are going to keep things simple. At this point for all effective discussion, we have taken triglycerides from the liver and delivered to the tissue in the form of LDL. Now that LDL receptor, what if it is deficient? This is not good.

    16:25 In the previous discussion, we looked at where the E-receptor was deficient. What is that called? E-receptor. I showed you how many lines? Three horizontal lines that were a kind of hypolipoproteinemia 1, 2, 3, and you have 3 horizontal lines to form an E. In this case if you have an LDL receptor deficiency, you all must know that this is a type II hypolipoproteinemia.

    16:51 If this is a type II hypolipoproteinemia, another name for this is called, well before you even memorize this which you should be doing to begin with, LDL is being accumulated in your circulation.

    17:03 What does LDL contain? It contains cholesterol. So, therefore, if cholesterol is being elevated, what do you call this when you have LDL receptor deficiency? Here you have, number 1, familial hypercholesterolemia type II. To repeat E at three, type III, you remember the other name for that. It was called familial dysbetalipoproteinemia. I don't care how you do this, but you must memorize the type E or of type III, which is the E receptor deficiency. It is called familial dysbetalipoprotenemia.

    17:32 Here we have familial hypercholesterolemia. What was type I? Type I in the previous discussion was the fact that you are missing capillary lipoprotein lipase. What did you require to stimulate the capillary lipoprotein lipase? C-II. So if C-II in lipoprotein lipase aren't present, what would be accumulating in your patient? Good. Tons of chylomicron. What does chylomicron contain? Tons of triglycerides. So what might you call type I? Hypertriglyceridemia.

    18:03 Is that clear? You see how it is important that you pay attention normal so that as you plug in the pathology all of these has come to life. Let us take a look at number 2. Once again bottom line is this, there was accumulation of type IV, accumulation of VLDL. VLDL has one, two, three, four letters in it. Thus, accumulation of VLDL, which also contains triglyceride, will be a type IV hyperlipoproteinemia. And this may either be primary or secondary hypertriglyceridemia. Is that clear and how important is this? Very. The reason I say that is the following. Of all these hyperlipoproteinemias, which one seems to be a little bit more common? Once again in the United States, what is an epidemic? Obesity is an epidemic. What does that mean to you? Large amounts of lipids. What kind of lipid? Most are triglycerides and its mostly VLDL that is accumulating. Later on, in endocrinology, when we talk about diabetes mellitus and if there was enough insulin, we will understand that those patients who are obese and you have insulin resistance that that patient is going to have accumulation of increased VLDL. Take a look of this. What type of hyperlipoproteinemia is this? Type IV.

    19:24 Not to worry. All of this we are going to repeat over and over again. At this point, we are just giving you two schematics of which, how your patient and our bodies really handles and manages the lipid that is coming through our entire body either from the mouth or from the liver to the tissue. Let us continue. Now to summarize everything we just talked


    About the Lecture

    The lecture Hyperlipidemia by Carlo Raj, MD is from the course Atherosclerosis.


    Included Quiz Questions

    1. Duodenum
    2. Jejunum
    3. Mouth
    4. Stomach
    5. Ileum
    1. CCK
    2. Gastrin
    3. Secretin
    4. Motilin
    5. GIP
    1. Capillary lipoprotein lipase
    2. Hormone-sensitive lipase
    3. LCAT
    4. Pancreatic lipase
    5. Hepatic lipase
    1. HDL
    2. LDL
    3. VLDL
    4. IDL
    5. Chylomicrons
    1. VLDL
    2. HDL
    3. IDL
    4. LDL
    5. Chylomicrons

    Author of lecture Hyperlipidemia

     Carlo Raj, MD

    Carlo Raj, MD


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    Teaching style builds on itself
    By Neuer N. on 21. June 2018 for Hyperlipidemia

    I really found the teaching methods used here beneficial. He'd go through the pathway and emphasizing key steps, then point out where they'll be important down the line, then come back to continue the pathway. The repetition helped so that when he taught the disease I knew why it was resulting in that outcome. Really a fan of it. Also, keep the memory cues coming.

     
    Difficult to follow:
    By sidra m. on 23. October 2017 for Hyperlipidemia

    -There was alot of jumping ahead and then circling back to the same point which made what should have been a 19 minute lecture, took about an hours lecture with all the pausing, going through transcripts and even looking up certain references myself to complete this lecture. The whole point of lecturio is high yield learning in a timely fashion. I appreciate the effort done and liked his style of teaching enthusiasm, however there needs to be less going off on tangents before the point has been made.