Interpret Serum Lipid Profiles

And this risk factor, we need to understand also the pathophysiology of atherosclerosis because atherosclerosis is the underlying etiology for most of the coronary artery disease, not all of them, but most of the coronary artery disease. Uh, we also call it ischemic heart disease. It has also other names, atherosclerotic cardiovascular disease, because the underlying cause is atherosclerosis. So, how does atherosclerosis happen? When we are born, our arteries are clean. We don't have any uh fatty streaks or any atherosclerosis. With time, what happens? The cholesterol, and mainly the LDL cholesterol, with some dysfunction of the endothelium, they get infiltrated inside the subendothelial intima. Why LDL cholesterol? Because they are small in size and also because they get modified, they get oxidized. So, the oxidized LDL with endothelial dysfunction, they get inside the subendothelial intima, and over there, they recruit monocytes or macrophages. The macrophages engulf this oxidized LDL and they cannot like destroy this oxidized LDL. So, they undergo morphological changes. So, they become foam cells. With time, these foam cells, which is the macrophage with oxidized LDL, and also smooth muscle cells of the endothelium, some of them also uh, they engulf oxidized LDL. So, with time, this forms what we call it fatty streak. So, there are three components for the uh, formation of this fatty streak. The main one is the LDL uh, cholesterol, which is get oxidized. The second one, dysfunction of the endothelium, because for this LDL to get inside, it needs some kind of permeability, even though they are very small particles. The third is the immune cell. Atherosclerosis is a multifactorial pathology with involvement of different factors, and the progression depends on the different risk factors. So, high level of triglycerides usually it uh, creates an inflammatory component of the atherosclerosis. So, patients who have a high level of triglycerides, the progression of atherosclerosis on those patients is more rapid than the progression of atherosclerosis in uh, patients with normal triglyceride cholesterol. Patients who have a high level of LDL cholesterol, of course, the probability of the for the development, of course, for those patients is higher, simply because LDL cholesterol and the oxidized LDL cholesterol, it is the cornerstone for the development of atherosclerosis. The HDL cholesterol has a different role because HDL cholesterol's main function is to reverse cholesterol transport. So, it takes the cholesterol from the peripheral tissue to the liver. So, it reduces the, the risk of accumulation of cholesterol in the peripheral tissue. So, patients with a high level of HDL cholesterol, they are kind of more protective. Nowadays, even there is a more emerging role of HDL cholesterol. They, they realized that or the studies discovered that HDL cholesterol has an anti-inflammatory effect, and it also has an antioxidant effect. And since oxidation of cholesterol is one of the major components in the pathogenesis of atherosclerosis, all the antioxidants involving HDL cholesterol are protecting or delaying the progression of atherosclerosis. And also, they found that it has some anti-thrombotic effect or antioxidant effect. Because so, what happens? I, I told you the story until we get the fatty streak, and then we, we, we got the, the uh, athero or atherosclerosis. So, what happens? Why these atherosclerosis or this fatty streak can lead to coronary artery disease? At some point, these atherosclerosis become bulky and it has what we call it a fibrous cap, and inside these foam cells undergo apoptosis. So, we get a fibrous tissue, and with the turbulence of the uh, blood flow, or with more like, with more other risk factors, like for example, people with high blood pressure. So, this cap can get torn. When this cap of the atherosclerosis gets torn, it will expose the subendothelial area, and immediately this can lead to thrombosis, and this thrombosis will lead to narrowing or complete blockage of the artery. And here, the patient developed the symptoms of ischemia due to the blockage. So, it is not only atherosclerosis. Atherosclerosis is the predisposing factor. But over the atherosclerosis, the patient may get thrombosis, and then the thrombosis is the main reason for the for the uh, blockage or narrowing of the coronary artery disease and development of the ischemic symptoms of myocardial infarction. So, this process occurs over years. It may take more than 10, 15 to 20 years, and the progression depends on the risk factors. If your triglyceride is high, that means the progression will be rapid. If LDL is higher, this also increases the uh, progression. HDL cholesterol is lower, this increases risk. So, this is the lipid triad: high triglyceride, high LDL cholesterol, low HDL cholesterol. All together, they are increasing the risk for the development of the uh, coronary artery disease. Epidemiological evidence, cholesterol is a negative risk factor, as I said, it has anti-inflammatory, it has anti-oxidant, and it may even have some anti-fibrolytic effect. What other risk factors? Risk factors of the lipid triad. It has a direct connection with the development of atherosclerosis. What other risks? First is the family history of CAD. If the patient has a family history of CAD, he will have a higher risk compared to a patient without a family history of CAD. Why? Because maybe there's a genetic component. Uh, uh, maybe they have some genetic issue with the uh, endothelial lining, because as I told you, it is three components: the immune cell, the LDL stores or lipids, and the endothelial dysfunction. So, those three play together for the development of atherosclerosis. So, family history is one of the important components because it can affect the immune cells. It can affect the level of LDL cholesterol, as we will see during, or we have seen in the previous lecture, that there are some genetic predispositions for familial hypercholesterolemia, and especially if the family history for the coronary artery disease developed in young age, and if a patient relative, his father or his mother or any first-degree relative, developed coronary artery disease before, for example, age of 30. This is like an alarm. So, this patient immediately needs screening. Lifestyle risk factors. The life major risk factor for development of atherosclerosis because it leads to obesity and it can affect the other stuff. So, accidental lifestyle, lack of exercise, the bad food habit, and in the previous lecture, we talked that most of the cholesterol is not dietary, it is endogenous, but still the dietary cholesterol and dietary triglyceride play a role in the development of atherosclerosis. Talk about lifestyle. When we talk about lifestyle, we talk mainly about exercise, lack of exercise, and about the uh, bad food habit. Age, as we said, it is about lipoprotein lipid profile, and also it is about endothelial dysfunction. So, with age, the endothelium is not like it's getting more dysfunctional than in younger people, and also the immune system and the immune cells, also the immune system is getting older. So, with age, the risk for development of cardiovascular disease or atherosclerotic cardiovascular disease increases. Type two diabetes. Type two diabetes is one of the major risk factors for development of atherosclerotic cardiovascular disease because patients with type two diabetes have a unique lipid profile. They have high levels of triglycerides, which is increasing the risk of atherosclerosis because it gets involved in the inflammatory component, and also because they have what we call small dense LDL cholesterol particles. So, this is like a very specific LDL particle which is unique for patients with type two diabetes, and the studies have shown that the presence of these small dense LDL cholesterol increases the risk of development of atherosclerosis. Obesity. Obesity is always one of the risk factors for atherosclerosis because with obesity, usually we have what we call metabolic syndrome, and people with metabolic syndrome and obesity, they also have a special lipid profile. Usually, they have high levels of VLDL triglycerides, like patients with type two diabetes, and this increases their risk for development of development of atherosclerosis. Also, patients with metabolic syndrome usually develop hypertension, and hypertension is also one of the risk factors. So, then hypertension. Hypertension is one of the major risk factors, and as I said, because it affects the blood flow, and the disturbance in the blood flow could be one of the risks for the tearing of the fibrous cap of atherosclerotic plaque, and then the cigarette smoking. Cigarette smoking is one of the major risk factors for development of atherosclerosis, like cigarette or shisha or whatever, because it increases systemic inflammation and it increases the level of fibrinogen. And as I mentioned, the blockage of the coronary artery doesn't happen only from the atherosclerosis, but it occurs usually due to the tear of the fibrous cap and the exposure of subendothelial intima to the blood flow, and this exposure leads to interaction between fibrinogen and between subendothelial tissue and leads to the development of a thrombus, and this thrombus is the main underlying cause for the blockage and narrowing of the coronary artery disease. So, there are other risk factors. I mean, when we have a patient with coronary artery disease, we screen for all these risk factors. We ask about family history. We ask if he smokes or not. We ask about sedentary life. We measure lipoprotein profile. We measure blood glucose. We ask about history of diabetes or hypertension. All these we call them like classical risk factors. But there are sometimes patients who come with coronary artery disease, and all these risk factors, they are normal. They have normal lipid profile. They are not smokers, not obese. They have a healthy lifestyle. Here, we have to look at non-classical risk factors. One of these non-classical risk factors is lipoprotein(a). And as I mentioned in the resource session, lipoprotein(a) has been discovered recently, like in a couple of decades, and it has shown that it doesn't respond to treatment and it has a genetic predisposition. So, it is genetically determined. So, if you are born with a high level of lipoprotein(a), it means that you have a higher risk for developing cardiovascular disease. And if you are born with a lower risk, lower level of lipoprotein(a), it means that you have a lower risk. The other thing is the fibrinogen factors. So, we also look at this because some people have some abnormalities in the fibrinogen factors. Some people have like protein S deficiency, protein C deficiency, or have a problem with fibrinogen. And also, as I said, for example, smoking itself can affect the level of fibrinogen. The other risk factor is homocysteine. It's like an atypical risk factor because people or patients with a high level of homocysteine in the circulation can lead to damage and destruction of the endothelial lining or the endothelium. It is an interplay between lipid profile, endothelial dysfunction, and immune cell recruitment. So, homocysteine mainly affects the integrity of the endothelial cells, and patients with a high level of homocysteine get endothelial dysfunction, which facilitates the entrapment of LDL cholesterol particles into the subendothelial intima, where it can be engulfed or internalized by macrophages, which then get converted to foam cells, which is like the very early steps in atherosclerosis. Also, C-reactive protein. Over the last years, there is an emerging trend to classify atherosclerosis as a chronic inflammatory disease, and even there are huge studies that encourage using anti-inflammatory drugs for patients with atherosclerosis, and those drugs have shown that the level of C-reactive protein is predicting and it can be used as a prognostic marker for atherosclerosis. So, now, when we talk about atherosclerosis, yes, it is everything starts with lipids. Everything starts with LDL cholesterol, and over time, but we cannot deny the inflammatory component. Inflammation also plays a role to the extent that now we can classify atherosclerosis as a chronic inflammatory disease. So, C-reactive protein, which is an inflammatory marker, is one of the important risk factors for atherosclerosis, and as I said, there are many huge studies that have shown that anti-inflammatory drugs can delay the progression of atherosclerosis. Do you have any questions so far? Okay. So, this is uh, the table for different lipoproteins. Here, we, we'll just show that this is like the old name for lipoproteins, like they were calling them according to the band electrophoresis band, because what we do, we can put the plasma proteins in electrophoresis, we run them, and they will reach different distances based on their density and size, and the electrophoresis marker for chylomicrons is the omega band or omega protein. So, at the omega band, all the aggregated lipoproteins will be chylomicrons, and as you know, the major lipid component of chylomicrons are triglycerides, mainly the dietary triglycerides. For the LDL, the electrophoresis marker band is the beta, and the core of LDL cholesterol contains cholesteryl esters. As for the VLDL, the band called pre-beta, and as we know, the VLDL contains triglycerides, mainly containing triglycerides, it has cholesterol, but mainly contains triglycerides, which is endogenously synthesized in the liver. And chylomicrons, they are more or less similar, they are, their metabolism is more or less similar, and their components, they mainly transport triglycerides. The main difference between chylomicrons and VLDL is that chylomicrons are transporting the dietary triglycerides from the intestine to extrahepatic tissues, while VLDL is transporting triglycerides from the liver, endogenously synthesized in the liver, to extrahepatic tissues. So, more or less, they have a similar function, but they have different destinations. Chylomicrons start from the intestine, while VLDL starts from the liver. The HDL, the final one, the electrophoretic marker for HDL is called alpha band, and HDL has a high level of cholesterol. So, HDL and LDL also, they have a similar core of lipids. Both of them, they have cholesteryl esters. But the difference between LDL and between HDL is that HDL is mainly taking the cholesterol from the extrahepatic tissue to the liver. So, what we call it reverse cholesterol transport. The second thing is about the screening for dyslipidemia. When we screen people for dyslipidemia, and someone could ask a question, but why we just, why we don't just screen everyone to be safe and to be 100% sure we will pick up every patient with dyslipidemia? And theoretically, that is true. But is it affordable to screen everyone for dyslipidemia? Why usually we set criteria for screening? It's mainly for two reasons. The first thing, the cost. We set criteria because this screening program usually it is free. Usually. So, who will pay for it? It is the government. It is the state. That means we need to reduce the cost to have a balance between picking patients at risk and at the same time not having very high costs. And here comes the recommendation for screening. And it keeps this balance in a good shape by setting very clear recommendations that make it easier to pick up people at risk and at the same time not necessarily making it not necessary to screen the whole population. So, here is the recommendation. Children more than two years, as I said, less than two years, I told you when, like the newborn, they don't have cholesterol in their arteries, and that's why up to two years, we don't need to screen them, even if they have like familial hypercholesterolemia or whatever, it will not reach that level by two years, and that's why below two, we don't screen. So, between two and 16, what is the role? We screen only if there is hypertension, diabetes, obesity, smoking. So, I mean, it's very unlikely, of course, to have a child start smoking before 16 years, but still, it is in the recommendation, or positive family history of coronary artery disease. So, any child between two years to 16 years who has hypertension or diabetes or morbid obesity or smoker or having a positive family history, we have to screen them for dyslipidemia. Three. After 16 years old, everyone should get screened once at least. Yeah. Any adult of age more than 16 years old should have had his or her lipoprotein profile at least once. Why? Because if there is any abnormality, very high level of triglycerides, very high level of LDL cholesterol, very high level of lipoprotein(a), then the measures will start earlier to protect him or her from developing atherosclerosis. Type four, for the adult from 20 years until 75 years. What is the regulation? If there is no risk of coronary artery disease, and what does it mean? If there is no hypertension, no diabetes, not obese, no smoker, blah blah blah blah, they need to screen every five years. 20 at least every five years, lipoprotein profile. Even because this recommendation is different from country to country, but for you and your patient, you have to recommend them to do this screening every five years, even if they don't have any risk factors for coronary artery disease, at least every five years, they should check their lipoprotein profile. If there is a family history of coronary artery disease, that means it should be less frequent, every two years, every two years to check the profile. Type five, adult more than 75. Screen only if there are multiple risk factors for coronary arteries. And if the patient reaches 75 years old without developing atherosclerosis, it is unlikely to develop atherosclerosis after that age, except if he or she has multiple risk factors. Between two to 16 years, more than 16 years, and then between 20 to 75 years, and more than 75 years. So, this is the guidelines and recommendations for screening of dyslipidemia in different age groups. How we do a screening? You have to get screened for lipid profile. How we do the screening? Usually, we ask the patient to get fasting between 12 to 14 hours from 8:00 early dinner from 8:00 until the morning when she or he gives a blood sample before you consume fasting. Type, you will get some common questions from the patient. They will ask you, okay, can we drink water? Yes, they can drink water. It's fine. Others will ask you, can we just drink coffee in the morning before we come to the clinic? No. No coffee. The only allowed thing to have is water. Okay. Type 12 to 14 fasting is essential. When? And that means we can also have non-fasting two types of lipid profile. Fasting is preferable. Usually, if you are screening or if you are thinking about something or if you have any doubt that your patient has a high level of lipid profile, so fasting is preferable. But sometimes you can take non-fasting, but if non-fasting cholesterol was more than 5.2 millimolar, and the LDL cholesterol is less than 0.9 millimolar, then you will do fasting. And that's why it's better to start with fasting from the beginning because if the non-fasting result was non-conclusive, you will need to do the fasting. Coronary artery disease or peripheral vascular disease. If the patient has coronary artery disease or peripheral vascular disease, then the sample should be fasting. Diabetes, glucose intolerance, central obesity, hypoglycemia, hypertension, chronic renal failure, family history. So, if the patient has any of these risk factors, then the recommended screening test is a fasting sample. So, some patients, they already have diabetes mellitus, and it has criteria for diagnosis. And some patients, they have what we call glucose intolerance. And the difference is that patients with diabetes are diagnosed with diabetes due to specific criteria using hemoglobin A1c or fasting blood glucose or OGTT or whatever. But what does it mean that a patient has glucose intolerance? Is he diabetic or not diabetic? He's not diabetic because he doesn't fulfill the criteria to get diagnosed with diabetes, but at the same time, his fasting blood glucose level is above normal. So, it is like we call it borderline. And according to WHO classification, if the fasting blood glucose lies between 110 to 126 mg per deciliter, I mean, millimolar, this is considered borderline, and the patient will be considered glucose intolerant. Normal is less than 110. More than 126, we repeat the sample and then we can diagnose the patient with type 2 diabetes. But when we do lipid profile, we are mostly interested in LDL cholesterol and to some extent also total cholesterol. There are equations that we can estimate the LDL cholesterol by just having the total cholesterol, HDL cholesterol, or triglyceride. Called Friedewald equation. So, if you have the total cholesterol, and you have the HDL cholesterol, and you have triglyceride, you can calculate the LDL cholesterol, which will equal total cholesterol minus HDL cholesterol plus triglyceride divided by 2.2. So, using this equation, we can estimate LDL cholesterol. So, without directly measuring the LDL cholesterol. The problem with this equation is that it is not valid if the triglycerides are very high. If the triglyceride level of the patient is more than 400 mg, which equals 4.5 millimolar, then we cannot use this equation. So, what we use in this case? We measure what we call non-HDL, which is equal to total cholesterol minus HDL cholesterol. This non-HDL cholesterol is useful, especially in patients with very high triglyceride levels. Very high triglycerides. We don't only target LDL cholesterol, but we also look at non-HDL cholesterol, which is just the total cholesterol minus the HDL cholesterol. Why? Because this non-HDL cholesterol will include also the remnant chylomicrons, will include the IDL, and both of those in patients with high triglyceride levels, it means that their risk is high, and both can affect the progression of atherosclerosis. So, rule of thumb in patients with very high triglycerides, we measure non-HDL cholesterol. Assessment of dyslipidemia risk. What is the level that we look at to assess our, what is the average that we are using? Total cholesterol: normal, it should be less than 5.2. Borderline, between 5.2 to 6.2. High, if it is more than 6.2. And if the total cholesterol of the patient is more than 6.2 millimolar, we consider it high. For HDL cholesterol, between 0.8 to 1.1. Borderline, if it is less than 0.85, this will be considered high risk. We, as we said, it is a negative risk factor. The HDL cholesterol. LDL cholesterol, if it is more than 4.15 millimolar, this is high risk. Patient triglyceride, if it is more than 2.26, 26 millimolar, this is high risk patient. Also, the waist circumference. Waist circumference, we measure it to determine abdominal obesity because it determines the presence of or the amount of visceral adiposity, which is a major risk factor for insulin resistance. So, for men, 102 cm, higher than this is high risk. For women, it is 91.5 cm. So, circumference, we measure it for risk stratification, for the risk stratification of dyslipidemia. Secondary causes of dyslipidemia. Hypercholesterolemia. Secondary causes. Secondary causes. If we found a high level of cholesterol in the patient, we have to try to find if this is primary, this is primary, or it is secondary to other diseases. What are the secondary causes? High levels of total cholesterol and LDL cholesterol. Secondary causes could be hypothyroidism. Hypothyroidism is one of the diseases that lead to an increase in the level of LDL cholesterol and total cholesterol because it affects the level of LDL receptors. So, thyroid hormone increases LDL receptors. Patients with hypothyroidism, if they don't get the accurate treatment, this will affect the level of LDL receptors, it will lead to a lower level of LDL receptors, and this will increase the circulating LDL cholesterol and the total cholesterol. Also, patients with obstructive liver disease, this will affect the bile salt and bile, and also it will affect the cholesterol level. Nephrotic syndrome. Nephrotic syndrome, people lose a lot of protein, and this affects the level of cholesterol. Progesterone, anabolic steroid therapy, SLE, multiple myeloma. All these diseases are affecting the lipid metabolism or cholesterol metabolism and can lead to an increased level of total cholesterol. So, if you have a patient with a high level of total cholesterol, you also have to think about the secondary causes. What would be the cause of these high levels of cholesterol? If the patient doesn't have any, like no sedentary lifestyle, he's exercising well, he has good dietary habits. So, you have to think about secondary causes. What about triglyceride and VLDL cholesterol? They are increased in type 2 diabetes, as we mentioned before, chronic renal failure, in hypothyroidism itself, during pregnancy, obesity, as we know, oral contraceptives, estrogen, corticosteroids also affect this, excessive alcohol intake, beta-blockers, thiazide diuretics. All these different diseases and drugs can increase triglyceride and VLDL cholesterol. So, you also, for example, when you follow up your patient after giving the diuretics and beta-blockers, you have to follow up with their lipid profile. You should have a baseline lipid profile and then follow up to see how their treatment is affecting their lipid profile. Low HDL. In hypertriglyceridemia, it affects the HDL cholesterol. Anabolic steroids, cigarette smoking, as we mentioned before, it affects the HDL cholesterol and it can, through HDL cholesterol reduction, it can increase the risk for atherosclerosis. Sedentary lifestyle also affects HDL cholesterol and post-major surgical procedures. All these are the secondary causes. So, you have to think about these secondary causes and you have to have them in your mind when you manage your patient with dyslipidemia. Type, how we manage dyslipidemia? What is the goal when we add drugs, when we increase the dose of the drug, when we use more than one drug? What is the criteria for the medical and non-medical therapy of dyslipidemia? So, the management of dyslipidemia is mainly based on the level of LDL cholesterol. Okay. If you have a patient who has less than two risk factors, non-hypertensive, for example, non-diabetic, non-obese, mild risk factors, for example, only smoking, how you will manage it? If their LDL cholesterol is more than 4.1 millimolar, we will just recommend nutritional guidelines. We refer them to a nutritionist for changing their dietary habits, and we recommend physical activity. And if it's less than two risk factors, we only depend on lifestyle modification if their LDL cholesterol is more than 4.15 millimolar. Type, if these patients come, for example, after one month or two months, and we find that their LDL cholesterol becomes more than 4.9 millimolar, here we immediately start treatment, which usually we start with statins. So, we start immediately with statins, low dose of statin, like 10 milligrams atorvastatin, and then you will ask the patient to come after one month or two months. What will be your target? What is the target of drug treatment? Our target is to reduce LDL cholesterol to less than 4.1 millimolar. So, after two months, for example, we come to you, and you find that his LDL cholesterol becomes less than 4.1 millimolar, it means that okay, it's under control. Statin 10 milligrams is good for him, so he should continue or she should continue on statin 10 milligrams. But the patient might ask you, but doctor, now my LDL cholesterol is normal. Should I stop the statin? No. When we start the statin, it means it is more or less for life. So, we ask the patient to continue in the same dose, and we will follow up the level of LDL cholesterol. So, what if the patient after two months comes with LDL cholesterol more than 4.1 millimolar? In this case, we increase the dose until we reach our target. And the same, if the patient has more than two risk factors, then the target for starting the lifestyle modification is reduced. It becomes 3.3 millimolar. So, we intervene at 3.3 millimolar with nutrition or dietary changing or dietary modification and physical activity. If it reaches more than 4.1 millimolar, we start the treatment, and our target will be less than 3.36 millimolar. If the patient has already atherosclerosis and patient diagnosed with myocardial infarction or angina, and there is a proof that there is atherosclerosis here, the nutritional and lifestyle modification is started earlier if the LDL cholesterol is more than 2.59 millimolar, and drug therapy starts at 3.36 millimolar, and our goal is 2.5 millimolar. So, here we usually use aggressive drug therapy. So, even statin alone may not be enough. We add other drugs. For example, there is a drug called ezetimibe, which blocks the absorption of cholesterol from the intestine. So, it works with a completely different mechanism of action than statins. And now also there is another drug called PCSK9 inhibitor, that also is used for aggressive treatment when our goal is to reach less than 2.5 millimolar, because this can sometimes not be achievable by statin only. If the patient has diabetes, it is the same as CAD. So, any patient with diabetes with LDL cholesterol more than 3.3 millimolar should start treatment, and the goal for diabetic is 2.59 millimolar, less than 2.59 millimolar. So, this is how we manage dyslipidemia. And what if the management based on HDL cholesterol? It's not common. Usually, the management is based on the LDL cholesterol. But if the management is based on HDL cholesterol, we consider weight loss, physical activity, and smoking cessation lifestyle modification. We start if the HDL cholesterol is less than 0.9 millimolar in males, and if it is less than 1.16 millimolar in females. Okay. If it is less than 0.9 millimolar, and the patient has risk factors for LDL cholesterol is high or family history or whatever, we start immediately drug. What is the goal? To increase HDL cholesterol more than 0.9 millimolar in case of strong family history, and more than 1.16 millimolar if the patient has coronary artery disease. And for the female, the same, it should be less than 1.16 millimolar. If it is less than 1.16 millimolar, we start the drug. And the same criteria, more than 1.16 millimolar will be the target of the drug therapy. If there is a strong family history and if the patient has cardiovascular disease or coronary artery disease already, our goal will be to increase their cholesterol to more than 1.42 millimolar. And the last thing today is hypertriglyceridemia. If you remember from my lecture, lipoprotein lipase is an enzyme that is anchored to the capillaries in the adipose tissue, and its function is to metabolize VLDL and chylomicrons. So, it is a lipase. So, it destroys or it breaks down triglycerides into free fatty acids and monoglycerides to be taken by adipocytes. And the presence of this lipoprotein lipase is very important for the triglyceride-rich lipoproteins, which are chylomicrons and VLDL. Patients who have deficiency or problems with lipoprotein lipase. So, what will happen if the patient doesn't have lipase or the activity of this enzyme is low? What will happen? That this patient will present with very high levels of chylomicrons, and we call it chylomicronemia syndrome or very high levels of triglycerides. So, how do we diagnose them? To diagnose them, we do what we call the heparin test. Why heparin? Because injection of heparin releases the lipoprotein lipase from its attachment or binding to the capillary. And why we want it to get displaced from the capillary? Because we want to measure the activity of the lipase. We cannot measure it inside the artery. We need to have this lipoprotein lipase in our blood sample. So, first, we give heparin, and then we take the plasma sample, and then we measure the lipoprotein lipase activity. And if there is low activity of lipoprotein lipase, following this is the features of several conditions, particularly type one hyperlipoproteinemia, here what we call it familial hyperchylomicronemia or the chylomicronemia syndrome. So, this occurs due to deficiency or low activity of lipoprotein lipase. To diagnose it, we need to remove or release lipoprotein lipase from the capillaries. How we do that? We give heparin, and we wait, and then we take the plasma sample, which will contain the released lipase. Then we measure the activity. If the activity is low, this goes with type one hyperlipoproteinemia. And here is the clinical approach to the classification of hyperlipidemia. Here it shows how the lipoprotein appearance would look like. Here is the supernatant. It usually contains chylomicrons and VLDL. Here is the infranatant, which usually contains HDL and LDL. So, it depends on the density. The very low density is sitting up. The higher density is going down. And here we have cells and the breast. Here is in different types of lipid elevation. How the plasma looks like when we look at it. For example, in type one, very high level of chylomicrons. The infranatant will be clear, but the supernatant here will be cloudy because it will contain a lot of triglycerides, and so on. For LDL cholesterol and for triglycerides. Okay. So, I think you have questions. Who is having questions before we go to the second part of our lab? >> Dr. Do we inject the patient with heparin? >> Yes. >> Okay. If we inject the patient, then there will be other enzymes that are released from the capillaries, or it's only lipoprotein lipase? Is it specific for this? >> Maybe other enzymes, but here, like our aim is to measure the activity of lipoprotein lipase. Even if other enzymes are released, we will not, we will not care about them because after taking the sample, we will only measure the activity of lipase. But maybe there are other enzymes that can be released. Um, I, I don't know. I'm not sure, maybe. But specifically for this test, we measure just the activity of lipoprotein lipase. So, even if there are other enzymes, because the test is very specific for the activity of lipoprotein lipase, so it will not affect the result. Any other questions? >> Uh, doctor, do we see the LDL in the supernatant layer? The LDL? >> Yes. >> No. Because, I mean, if you remember from our classification of the lipoprotein, chylomicrons have the least density, that's why they are floating. And then the VLDL, the HDL, and LDL, they have high density. So, that's why they go down when we centrifuge, because this is after centrifugation, you will get anything with low density will go up. Anything with high density will go down. So, in the pellet layer >> somewhere, not in the pellet, but probably it will be with the infranatant and with HDL in the pellet. You have the cells, the breast, mainly. More questions? >> In the second part of the lab, we have four problems. Okay. We have four problems. Uh, now it is 9:54. So, you will have 15 minutes to go through the four problems and try to answer all the questions, and we will, we will meet here again. I will be present here, but we will go through these problems at 10:10. Okay. We will go through these problems one by one at 10:10. Please try to read them, try to interpret, because this is how exactly the question will come in your exam. So, this scenario is similar to the scenario that you will get in your exam. So, try to think about the different >> Doctor, um, are we going to be given the reference range in the exam? >> You will be given what? >> The reference range. >> Yeah. Yeah. Yeah. Always. Always. You don't need to memorize the reference. Never. I mean, I'm talking about myself. I'm not talking about anyone else, but for me, any question that I will give you, you will get the reference. You don't need to memorize the reference range. Okay. Okay. 15 minutes. We meet here again at 10:10 and we go through the questions. See you in 15 minutes. Hey, I'm back, and we start to see or to look at these different scenarios. Scenario 1: A 35-year-old man complained of frequent headache. He is a regular smoker, and his waist circumference is 115 cm. His blood pressure was 150 over 100. The report on his blood chemistry was fasting blood glucose 5.3, serum total cholesterol 7.8, serum HDL cholesterol 0.7, serum LDL cholesterol 6.3, and serum triglyceride 1.6. What are the biochemical abnormalities in this profile? What are the biochemical abnormalities in this profile? Yes. High LDL cholesterol. Yes. High LDL cholesterol. Yes. And what else? Yes. Total cholesterol is high. Abnormalities. Would you consider this patient obese? And why? Obesity. Or not. Both are acceptable. Absolutely both are acceptable. Body mass index, waist circumference. Acceptable. Type. What lifestyle changes would you advise this patient to adopt? Diet modification. Yes. Physical activity. Yes. Low-fat diet. Yes. Exercise and diet. Yes. Stop smoking modifications. Stop to stop smoking. Uh, to be considered lifestyle modification. Type, if he has children, how often should they be screened for coronary artery disease risk? What is the recommendation for screening? Then we say to reduce salt intake to reduce one of the risk factors, which is hypertension. Yes, we can. Uh-huh. I'm screening the children. Screen children. If children 3 to 15 years, only if there are risk factors. Are you recommending to screen or not? Only if there are risk factors. Factor, risk factors. If the child himself is having risk factors, uh, coronary, coronary artery disease risk factors. Mhm. Or hypertension and high risk for CAD. As what do you think the cause of low HDL? Mhm. Smoking. Yes. Smoking. I will put it in factors. Mhm. Does not have a positive coronary artery disease. Scenario who have a risk for coronary artery disease. We haven't confirmed this patient has coronary artery disease. How can we confirm it? Patient's artery disease or not. You need what? >> Family screening. >> Rare screening. Atherosclerosis. Angiography. Headache. Smoker. Confirmatory diagnosis in coronary artery disease. What we have here is dyslipidemia is high, is low. Atherosclerosis. Children. What were the criteria for children? Criteria for screening. Children more than two years, adults less than 16 years are screened if there is hypertension, diabetes mellitus, obesity, smoking, or positive family history of coronary artery disease. Yes, you are right. Screening if a child himself or herself has hypertension, diabetes, or obesity, smoking, or family history of coronary artery disease, accordingly, you are right. A child, other than the history with hypertension and smoking, but not a child. But there is no need for screening. You are right. Scenario 2: A 30-year-old woman was admitted to the hospital because of abdominal pain. She was found to have xanthelasmas on her hand. She had no history of heart disease. Her blood chemistry results were fasting blood glucose 5.3, serum total cholesterol 8, serum HDL cholesterol 0.8, serum triglyceride 45. When her serum was refrigerated at 4 degrees Celsius for 18 hours, it developed a creamy layer on top of a clear infranatant. What are the biochemical abnormalities in this patient? Normal control? Yes. High total cholesterol, low HDL, and very high triglyceride. Between 2 and 1.8, and in this patient, it's 45. Very high or more than 50? Very high hypertriglyceridemia. Type. What is the possible cause of this abnormality? Very, very high level of triglyceride in the plasma. Mhm. What is the abnormality? Yes, you are right. What is the abnormality? Yes. Familial hypertriglyceridemia. Diabetes. Yes. High level of triglycerides. 45 is very high. Very high. Endothelial dysfunction. What will be dysfunctional to this level? Lipoprotein lipase deficiency. That is true. Has horrible tissue and it catabolizes triglycerides. Low lipase deficiency activity is low. Triglycerides will be very, very high in circulation. Almost probable cause, deficiency type. Which simulation test is needed to confirm the diagnosis? Which test? Injection. Yes. Heparin injection releases lipase, and then we take a plasma sample, and then we measure the activity of lipase. True. Type. Calculate the non-HDL cholesterol in this patient. Yes. Uh, yes, that's true. 7.2. It is very high. It is very recommended to calculate HDL cholesterol as a risk factor for cardiovascular disease. Patient admitted with abdominal pain. What could be the cause of abdominal pain in a patient with very high level of triglyceride that's complicated? Aneurysm? Cause? What is the common cause? Blockage in artery? High, very high level complication. Yes, acute pancreatitis. Patients with very high levels of triglycerides can develop acute pancreatitis due to acute pancreatitis. Very high levels of triglycerides can lead to acute pancreatitis. Question number three: A 7-year-old child was admitted to the hospital for investigation. His urine output was 1.5 liters per 24 hours, and his laboratory results were alas 5.3, serum total cholesterol 12.5, serum triglyceride 1.5, serum total protein 10, serum albumin 12. What a 24-hour urine protein? 4.5. What are the biochemical abnormalities in this profile? Abnormalities in this profile: High total cholesterol, low HDL, low total protein, low albumin, high protein in urine. What is the possible cause of all these abnormalities together? High urine protein, 24-hour protein collection, conditional edema. What is the cause of edema? Patient's edema? >> Kidney dysfunction. >> Kidney dysfunction. Yes. Like how the kidney dysfunction led to edema? Nephrotic syndrome. True. It is nephrotic syndrome. Loss of protein in urine. Loss of protein in urine. Reduction of the circulating albumin and total protein. Effect on plasma oncotic pressure. How this can lead to edema? Edema due to loss of oncotic pressure. True. Pressure. And why pressure is reduced? Pressure. Between edema. Very clear fluid will move from the intravascular to the interstitial space. Very clear. Level of cholesterol. What could be the reason? >> Percentage of total cholesterol. Yes, you are right. More concentrated. Absolute value. I like your way of thinking. Is it because of the liver? >> Yes. What happened in the liver? It's all about the liver. But what happened? Liver increases protein synthesis due to low protein level. So, more like protein. True. That's true. A liver tries to compensate from the liver tries to compensate and increase the protein in general, and with this increase, consequently, LDL will increase. Good, good, good, good, good. Scenario 4: A 56-year-old man was being investigated as he was habitually drinking alcohol and on a high-fat and carb diet with minimum physical activity. His blood chemistry results were fasting blood glucose 10.3, serum total cholesterol 11.5, serum triglyceride 4.5. What are the biochemical abnormalities in this profile? What are the abnormalities? High fasting glucose. Yes. High triglycerides. Yes. What is the possible cause for this abnormality? Until the patient ends high level of triglycerides and endogenous hypoglycemia or hypertriglyceridemia. What would be the possible cause? Mhm. Yes. Diabetes. Level of diabetes. Which cholesterol fraction should be assessed and why? Patient with diabetes and hypertriglyceridemia. Yes. Chylomicrons. Yes. HDL. Yes. LDL cholesterol. It means by another way, HDL cholesterol. Having been interested in triglyceride cholesterol. Any patient we focus fasting. With fasting for how long a patient should be fasting? Yes. Fasting. Very high level of fasting sample essential. Fasting between 12 to 14 hours. Here is the answers. Blah blah blah blah blah. It's football. HDL, triglyceride high. Yes. Indication for what? Triglyceride test. Yes. LDL with a P badge indication. >> Yes. Risk for atherosclerosis. Atherosclerosis risk factor. High level of LDL cholesterol. Second important, what we call it remnant cholesterol. Yes. High level of triglyceride. Patient is already into high level of triglyceride. Indication for cholesterol development of atherosclerosis. Triglyceride enhances inflammatory component of atherosclerosis. High level of triglycerides. Reduce the LDL cholesterol, but also to reduce remnant cholesterol, which includes not only cholesterol, but it includes the IDL, includes remnant chylomicrons. Within therapeutic target. Why? Why we look for non-HDL cholesterol? He will get statins and everything will be fine. High level of cholesterol, high level of LDL cholesterol, high level of triglycerides. We will think about reducing LDL cholesterol, but also reduce remnant cholesterol, which is non-HDL cholesterol. Risk of atherosclerosis was mainly developed due to high level of LDL cholesterol and way of thinking for many years. Studies showed that non-HDL risk patient, although cholesterol becomes normal, but it's still a kind of risk to develop atherosclerosis and still they develop atherosclerosis. Very low density lipoprotein cholesterol that you need to consider to protect a patient from developing atherosclerosis. What they call it remnant cholesterol. Smoking. You can, you can search and read about cholesterol, cholesterol, cholesterol, triglyceride-rich lipoproteins, LDL, and to estimate them, you need to look at non-HDL cholesterol. Lowering LDL cholesterol might not be enough for some patients, not for all patients, but for some patients. Interpretation. Believe me, cause of death in the world. Here it's not cancer. It's not war. It's cardiovascular disease. And to understand cardiovascular disease, you need to understand the lipoprotein profile. The more you understand how to interpret and how lipoprotein metabolism works, the more you will understand how to protect and how to treat patients with dyslipidemia and cardiovascular disease. High-density lipoprotein metabolism. It is composed. Okay. And it came from the intestine and from the liver. From where? Exchange. I will update. I will update it. Resource lecture. I will update it, Inshallah. And in that one, I talk about LCAT, cholesterol transferase enzyme, exchange between HDL, between other proteins like VLDL and HDL, mainly cholesterol transport. Cholesterol from the extrahepatic tissue to the liver, but also the HDL takes the cholesterol from other lipoproteins, from the VLDL and from the chylomicrons in exchange for triglycerides. Cholesterol transferase. Cholesterol transfer because it's an enzyme that exchanges the cholesterol between HDL and between other lipoproteins. HDL. When this cholesterol gets inside the HDL, HDL2, HDL3. HDL2 and less cholesterol. HDL3. You know how in the liver, P1, how the cholesterol is taken up by receptors? Is it ABCA1 or ABC? Cholesterol metabolism, how LCAT works and how it exchanges the cholesterol and alpha metabolism where the HDL cholesterol comes in contact with the receptors and the cholesterol is taken through SR-B1 receptor. Uh, I will update. And if you have more information about HDL metabolism, you are right, Muhammad. Mhm. More questions? >> Uh, doctor, I have another question. Doctor, you said in the record that whenever the cholesterol increases in other lipoproteins, HDL takes this cholesterol. But how HDL knows that there is high cholesterol? >> No, no, it is not. If I said it that way, it's not. HDL cannot solve the problem of hypercholesterolemia. It is not. It cannot solve any problem of hypercholesterolemia. The exchange between the cholesterol in other lipoproteins and HDL is a continuous process. As long as we have circulating HDL and we have circulating VLDL and chylomicrons, there is always escape of cholesterol. HDL takes this cholesterol and gives triglycerides through the enzyme LCAT. But if the cholesterol level is very high in the LDL or is very high in the chylomicrons, HDL cannot solve the problem, otherwise we would not need medication. Like this is part of normal metabolism. The cholesterol is taken from chylomicrons and VLDL to HDL through the LCAT enzyme. Any questions? Still we have time. Thanks for the opportunity. That's it for today. Uh, and we will meet again, Inshallah, in, I think, in problem 8, when we talk about the cardiac enzyme business. Uh, and then we will meet also in the last problem, I think, when we will talk about integration of the whole metabolism, and that would be, Inshallah, interesting resource. Okay. Thank you very much for being here for almost two hours, and see you, Inshallah, in the next lab.