پاورپوینت لیپید از هاریسون و سسیل

Disorders of Lipid & Metabolism Dr. Alireza Arefzadeh Assistant Prof of Endocrinology Tehran Medical Sciences Islamic Azad University Farhikhtegan Hospital References Cecil Essentials of Medicine. Harrison Hyperlipidemia is associated with increase risk of atherosclerosis related diseases like IHD and stroke LIPID AND LIPOPRTEIN METABOLISM  Major plasma lipids—cholesterol TG phospholipids FFA  Cholesterol is a major component of cell membranes and a precursor of steroid hormones and bile acids  TG are bodies major energy store particularly in adipose tissues  Cholesterol + TG are relatively insoluble in plasma and are transported as lipoproteins  Nomenclature of the lipoprteins is based on their separation by density gradient HDL: High Density Lipoprotein LDL: Low Density Lipoprotein VLDL: Very Low Density Lipoprotein IDL: Intermediate Density Lipoprotein  Because lipid molecules (cholesterol and TGs) are water insoluble, they must be packaged in special molecular complexes known as lipoproteins in order to be transported in plasma. Lipoproteins may accumulate in the plasma due to overproduction and/or deficient removal  Chylomicrons have a high content of lipid , are large and least dense  Lipoproteins transport absorbed dietary fat and endogenously synthesised cholesterol and TG Lipoprotein pathway is simplified in 3 main pathway 1--Exogenous pathway---lipids from food 2--Endogenous pathway ---lipids synthesised by the liver 3--Reverse cholesterol transport---return of cholesterol from tissues to liver Lipoproteins  1. Core: TG + Cholesteryle esters  2. Surface: Free Cholesterol + Surface Phospholipid + Apo Protein  Lipoproteins are complex particles with a central core containing cholesterol esters and triglycerides surrounded by free cholesterol, phospholipids, and apolipoproteins, which facilitate lipoprotein formation and function. Islamic Azad University بیوشمی و ساختارلیپیدها ساختارهای شیمیایی اسیدهای چرب بر اساس طول زنجیره هیدروکربنی ،تعداد اتمهای کربن و تعداد پیوندهای دوگانه مشخص میشوند: 1.اسید چرب اشباع شده که فاقد پیوند دوگانه است. 2.اسید چرب اشباع نشده که یک و یا بیش از یک پیوند دوگانه دارند؛ مانند امگا 3 -که نوعی اسید چرب غیر اشباع و ضروری میباشد ) از سوختها ( تنفس سلولیATP تولید NADH: nicotinamide adenine dinucleotide (NAD) + hydrogen (H).“ FAD(2H): flavin adenine dinucleotide DIAGNOSIS Dyslipidemia is defined by a total cholesterol, triglyceride, or LDL level greater than the 90th percentile or an HDL level lower than the 10th percentile for the general population. Because chylomicrons are present in plasma for up to 10 hours after a meal, fasting total cholesterol, triglyceride, and lipoprotein assessments are required for diagnosis. Low HDL Low HDL concentrations (<40 mg/dL) can also increase the risk for CHD. In the Framingham Heart Study, every decrease in HDL of 5 mg/dL increased the risk for myocardial infarction. Both lifestyle modifications (e.g., diet low in saturated fat, exercise) and pharmacologic therapy (e.g., nicotinic acid, fibrate) can improve HDL levels. However, target goals and treatment recommendations have not been established due to a lack of evidence. TREATMENT Treatment is initiated after two abnormal lipid findings. Treatment of elevated total cholesterol and LDL-cholesterol can slow the development and progression of CHD. TREATMENT The ASCVD Risk algorithm is used to calculate a 10-year risk of heart disease or stroke. This algorithm calculates risk by evaluating the following factors: 1.history of ASCVD 2. LDL-cholesterol levels 3. age 4. current diagnosis of diabetes 5.Gender 6. Race 7. total cholesterol 8. HDL-cholesterol levels 9. medication controlled hypertension 10. Smoking history Reference: Cecil Essentials 2022 TREATMENT History of the following conditions is considered as known ASCVD: 1. Acute coronary syndrome 2. Myocardial infarction 3. Stable angina 4. Coronary revascularization 5. Stroke 6.Transient ischemic attack 7. Peripheral arterial disease 8.Diabetes Mellitus 9. Abdominal Aortic Aneurysm 10. Symptomatic Carotid Artery Disease Reference: Cecil Essentials 2022 & Harrison TREATMENT High-risk patients may require additional agents to achieve target goals. Likely benefit of each agent needs to be balanced against potential adverse effects when determining drug therapy. In individuals younger than 40 years or with 10-year risk below 7.5%, lifestyle modification is recommended unless risk enhancers such as: 1. Family history of premature ASCVD 2. LDL-cholesterol greater than 160 mg/dL 3. Chronic kidney disease 4. Metabolic syndrome are noted. Reference: Cecil Essentials 2022 CHD risk factors  Age (men >45 years,women >55 years)  Family history of premature CHD (affected male first- degree relative <55 years or female first-degree relative<65 years of age)  Smoking  Hypertension  Low HDL(<40 mg/dL).  HDL concentrations higher than 60 mg/dL are  cardioprotective. CHD risk Equivalents Diabetes Mellitus Abdominal Aortic Aneurysm Symptomatic Carotid Artery Disease Peripheral Artery Disease ( PAD) Reference: Harrison The LDL cholesterol (LDL-C) estimation The LDL cholesterol (LDL-C) is then estimated using the following equation (the Friedewald formula): LDL-C = Total cholesterol – (TG/5) – HDL-C (The VLDL cholesterol content is estimated by dividing the plasma TG by 5, reflecting the ratio of TG to cholesterol in VLDL particles.) This formula is reasonably accurate if test results are obtained on fasting plasma and if the TG level does not exceed ∼200 mg/dL; by convention, it cannot be used if the TG level is >400 mg/dL. Reference: Harrison 2022 Treatment of HyperTG The serum triglyceride concentration can be stratified in terms of population percentiles and/or coronary risk: Normal — <150 mg/dL (1.7 mmol/L) Borderline high — 150 to 199 mg/dL (1.7 to 2.2 mmol/L) High — 200 to 499 mg/dL (2.3 to 5.6 mmol/L) Very high — ≥500 mg/dL (≥5.7 mmol/L) Treatment of HyperTG When triglycerides are borderline high (150 to 199 mg/dL emphasis should be upon weight reduction and increased physical activity. (Nonpharmacologic therapy) Treatment of HyperTG When triglycerides are high (200 to 499 mg/dL [2.3 to 5.7 mmol/L]), non-HDL cholesterol becomes a secondary target of therapy after LDL-C. In addition to nonpharmacologic therapy, drug therapy can be considered in highrisk patients, including those who have had an acute myocardial infarction, to reach the non-HDL cholesterol goals. These goals may be achieved by intensifying therapy with an LDL-C lowering drug, or by adding nicotinic acid or a fibrate. ('Pharmacologic therapy (including fish oil) above.) Treatment of HyperTG Treatment of HyperTG When triglycerides are very high (≥500 mg/dL), the initial goal is to prevent pancreatitis by lowering triglycerides with the combination of nonpharmacologic therapy and a triglyceride lowering drug such as a fibrate or nicotinic acid. Once triglycerides are below 500 mg/dL, LDL-C goals should be addressed. Treatment of HyperTG A fasting lipid panel is required to diagnose hypertriglyceridemia. Triglyceride levels higher than 200 mg/dL are classified as abnormal. Borderline triglyceride levels range from 150 to 200 mg/dL, and normal values are lower than 150 mg/dL. A diet and exercise program is recommended for all individuals with abnormal triglyceride levels. However, pharmacologic treatments to reduce triglyceride levels may be considered if fasting levels are higher than 200 mg/dL, especially if the individual is at risk for CHD or pancreatitis. Fibrates, fish oil, and nicotinic acid should be considered if the triglyceride level is higher than 500 mg/dL. However, for levels lower than 500 mg/dL, statins are first-line therapy. Reference: Essencial cecil 10 th Lifestyle modification  Lifestyle modification should be the initial step in the management of hyperlipidemia Lifestyle modification Restricting the dietary intake of fat lowers total cholesterol by approximately 15% and LDL cholesterol by 25%. Low-fat diets that limit saturated fat content promote LDL receptor expression and increase the uptake of LDLcholesterol from the circulation. By contrast, saturated fat downregulates hepatic LDL receptors and increases circulating LDL. Lifestyle modification Limiting the intake of saturated and transunsaturated fatty acids requires appropriate calorie substitutions. Increasing carbohydrate content to achieve this goal can increase the hepatic synthesis of triglyceride. Lifestyle modification Limiting the intake of saturated and transunsaturated fatty acids requires appropriate calorie substitutions. Increasing carbohydrate content to achieve this goal can increase the hepatic synthesis of triglyceride. Lifestyle modification Exercise has been shown to increase LPL activity. Even a single exercise session can reduce triglycerides and increase HDL. The impact of exercise on LDL is less clear. With low- to moderate intensity exercise regimens, clearance of VLDL particles increases LDL production. However, this effect is not seen with highintensity exercise programs. A decrease in LDL-cholesterol occurs with high-intensity exercise, and this effect is independent of weight loss. Dyslipidemia Management In patients with evidence of dyslipidemia, further evaluation and treatment are based on evidence of preexisting ASCVD and clinical assessment of cardiovascular risk using risk calculators such as the American HeartAssociation (AHA)/American College of Cardiology (ACC) risk calculator. For patients >40 years old without clinical CVD, the AHA/ACC risk calculator can be used to determine the 10-year absolute risk for CVD, and current guidelines suggest that a 10-year risk >7.5% merits consideration of statin therapy regardless of plasma LDL-C level. Reference: Harrison 2022 Dyslipidemia Management For younger patients, the assessment of lifetime risk of CVD may help inform the decision to start a statin, as well as a careful assessment of family history of ASCVD. In patients for whom the decision to start a statin is uncertain due to borderline ASCVD risk and/or borderline LDL-C levels, additional risk stratification might be considered. Blood tests that predict ASCVD risk beyond traditional risk factors include apoB, Lp(a), and high-sensitivity C-reactive protein (hs-CRP). In patients who are of a sufficient age (men >40 years and women >50 years), a coronary artery calcium (CAC) score has been shown to provide independent information about risk of CAD. Elevated levels of one or more of these biomarkers or an elevated coronary artery calcium (CAC) score might be used to justify initiation of statin therapy in primary prevention for patients who are in a borderlinezone with regard to treatment. Reference: Harrison 2022 ESC Guidelines 2019 ESC Guideline 2019 : Lipid Management in Diabetes Mellitus ACC Guidelines 2022 Pharmacotherapy If diet and exercise modifications do not sustain a normal lipid profile, then drug therapy is appropriate Pharmacotherapy The ASCVD Risk algorithm is used to calculate a 10-year Risk of heart disease or stroke. This algorithm calculates risk by evaluating the following factors: history of ASCVD, LDL-cholesterol levels, age, current diagnosis of diabetes, gender, race, total cholesterol, HDL-cholesterol levels, medication controlled hypertension, and smoking history. Web page Address https://tools.acc.org/ascvd-risk-estimator- plus/#!/calculate/estimate/ Pharmacotherapy History of the following conditions is considered as known ASCVD: Acute coronary syndrome, myocardial infarction, stable angina, coronary revascularization, stroke, transient ischemic attack, or peripheral arterial disease. Cardiovascular risk profile determines therapeutic plan including drug dosing and LDL targets in individuals 40 to 75 years of age. Pharmacotherapy High-risk patients may require additional agents to achieve target goals. Likely benefit of each agent needs to be balanced against potential adverse effects when determining drug therapy. In individuals younger than 40 years or with 10-year risk below 7.5%, lifestyle modification is recommended unless risk enhancers such as family history of premature ASCVD, LDL-cholesterol greater than 160 mg/dL, chronic kidney disease, and metabolic syndrome, are noted. AHA Guideline:Pharmacotherapy Figure 3 Expected clinical benefits of low-density lipoprotein cholesterol-lowering therapies. The expected clinical ... Eur Heart J, Volume 41, Issue 1, 1 January 2020, Pages 111–188, https://doi.org/10.1093/eurheartj/ehz455 The content of this slide may be subject to copyright: please see the slide notes for details. Fibric acid derivatives Fibric acid derivatives such as gemfibrozil and fenofibrate increase FFA oxidation in muscle and liver. The reduced lipogenesis in the liver decreases VLDL and subsequent LDL production. Fibric acid derivatives also enhance LPL activity and HDL synthesis. As a result, treatment is usually associated with not only lower triglyceride and LDL levels, but also higher HDL levels. Nicotinic acid Nicotinic acid has an antilipolytic effect and therefore decreases the influx of FFA to the liver. As a result, hepatic VLDL synthesis and LDL production are reduced Omega-3 Omega-3 fatty acids reduce VLDL production and subsequently lower triglyceride levels (by 35%). They also modestly increase HDL (3%) and LDL (5%). HMG-CoA reductase HMG-CoA reductase is the rate-limiting enzyme involved in cholesterol biosynthesis. Inhibition of this enzyme decreases intracellular cholesterol pools and subsequently increases uptake of LDL cholesterol from the circulation. HMG-CoA reductase inhibitors (e.g., lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, and rosuvastatin) increase cholesterol utilization, decrease VLDL synthesis, and increase HDL synthesis HMG-CoA reductase Treatment effects of statins can be assessed after 1 to 2 months. Additional agents can be considered if target goals are not achieved with maximal drug dosing. Reference: Cecil Essentials 2022 HMG-CoA reductase Adverse Effect of HMG-CoA reductase In the event of muscle symptoms, a plasma CK level may be obtained to differentiate myopathy from myalgia. Serum CK levels need not be monitored on a routine basis in patients taking statins because an elevated CK in the absence of symptoms does not predict the development of myopathy and does not necessarily suggest the need for discontinuing the drug. Statins can result in elevation in liver transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), but it is usually mild and transient and generally does not require discontinuation. Adverse Effect of HMG-CoA reductase Before treatment with Statin: Check Liver enzyme Then:2-3months and then Yearly Mild to moderate increasing of liver enzyme( 1-3 folds) without symptom does not need to discontinue statin. Increasing of liver enzyme more than 3 folds or symptomatic patients need to discontinue statin. Cholesterol absorption inhibitors Cholesterol absorption inhibitors (e.g., ezetimibe) function by interfering with the transport of cholesterol at the intestinal brush border. They increase cholesterol utilization and decrease LDL-cholesterol levels Cholesterol absorption inhibitors Ezetimibe is a Niemann-Pick C1 Like 1 (NPC1L1) inhibitor. NPC1L1 is a protein that aids in the transport of cholesterol across the intestinal brush border. Ezetimibe inhibits this enzyme, decreasing cholesterol absorption and thus increasing cholesterol utilization and decreasing LDL-cholesterol levels. Ezetimibe may be used as a single agent or in combination with an HMG-CoA reductase inhibitor to lower LDL-cholesterol levels. In combination with a statin, this agent may reduce cardiovascular events in highrisk individuals. PCSK9 inhibitors Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors represent an exciting new frontier in LDL-cholesterol reduction. PCSK9 is a protease whose function is the degradation of LDL receptors. Inhibition of this protease leads to increased LDL receptor survival, which in turn leads to the reduction of circulating LDL-cholesterol. The two approved agents, evolocumab and alirocumab, are both monoclonal antibodies against PCSK9 that are administered by subcutaneous injection every 2 to 4 weeks. They are indicated in patients with LDL greater than 190 mg/dL or ASCVD judged to be high risk who have not achieved desired LDL reduction on statin and ezetimibe. Cost of these therapies is significant and may be a limiting factor. Bempedoic acid Bempedoic acid inhibits adenosine triphosphate citrate lyase, an enzyme in the cholesterol biosynthesis pathway. This enzyme is upstream of 3-hydroxy-3methylglutarly-CoA reductase, the target of statin drugs. Bempedoic acid alone or in combination with other agents lowers LDL-cholesterol and is recommended for individuals intolerant to statins, unable to achieve target goals, and in circumstances where PCSK-9 inhibitors are not an option. Bempedoic acid Bempedoic acid is a new cholesterol-lowering agent that reduces cholesterol synthesis through inhibition of adenosine triphosphate citrate lyase, an enzyme upstream of HMG-CoA reductase in the cholesterol synthesis pathway. Bempedoic acid is a prodrug that is converted to its CoAactivated form by the very long chain acyl-CoA synthetase 1 Bempedoic acid In the United States, this nonstatin LDL cholesterollowering agent is approved for use as an adjunct to diet in patients with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia who, despite taking maximally tolerated statin dosages, do not achieve the desired LDLcholesterol target concentration.. Bempedoic acid Bempedoic acid has been approved as monotherapy (180 mg tablet once daily) and as a fixed-dose combination with ezetimibe (bempedoic acid, 180 mg/ezetimibe, 10 mg once daily). The Clear Harmony Trial was a phase 3 randomized, placebo-controlled trial that included patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both who were already on maximally tolerated statin therapy. A 12.6% reduction in LDL cholesterol was observed in the bempedoic acid group compared with a 1% increase in the placebo group. Another phase 3 randomized controlled clinical trial compared the LDL-cholesterol lowering of the fixed-dose combination of bempedoic acid and ezetimibe with that of bempedoic acid, ezetimibe, or placebo in patients with high risk of cardiovascular disease who were receiving maximally tolerated statin therapy after 12 weeks of therapy. This study showed a 36% decrease in LDL cholesterol in the group taking the fixed-dose combination of bempedoic acid and ezetimibe, 17% decrease in the bempedoic acid group, 23% decrease in the ezetimibe group, and 2% increase in the placebo group. The most frequently reported adverse effects for bempedoic acid monotherapy included hyperuricemia, gout, thrombocytopenia, leukopenia, and upper respiratory tract infections. Bile acid sequestrants Drugs that interfere with the absorption of cholesterol from the intestinal lumen increase cholesterol utilization and decreasecirculating levels of cholesterol. Bile acid sequestrants (e.g., cholestyramine, colestipol, and colesevelam) bind bile acids in the intestinal lumen and increase fecal excretion. Familial Hypercholesterolemia Mutations in the gene that encodes the LDL (apo B/E) receptor result in familial hypercholesterolemia. Impairment in LDL receptor synthesis or function decreases the clearance of LDL and increases circulating LDL levels, resulting in cholesterol plaque formation. Familial Hypercholesterolemia These plaques deposit in the arteries (atheroma), skin or tendons (xanthoma), eyelids (xanthelasma), and iris (corneal arcus). Familial Hypercholesterolemia Elevated total cholesterol (>300 mg/ dL) and LDL-cholesterol (>250 mg/dL) in an individual with a personal or family history of premature CHD and tendon xanthomas identifies patients at risk for familial hypercholesterolemia. Familial Hypercholesterolemia The homozygous form of the LDL receptor mutation is rare. Affected individuals present early in life with elevated levels of total cholesterol (600 to 1000 mg/dL) and LDL-cholesterol (550 to 950 mg/dL). Triglyceride and HDL-cholesterol levels are normal Familial Hypercholesterolemia The homozygous forms develop CHD, aortic stenosis due to atherosclerosis of the aortic root, and tendon xanthomas (often in the Achilles tendon). If the condition remains untreated, patients with homozygous familial hypercholesterolemia typically die of myocardial infarction before 20 years of age. Familial Hypercholesterolemia The heterozygous form of FH affects 1 in every 500 individuals. Partial receptor defect results in cells that display half the normal number of fully functional LDL receptors. These individuals have lower concentrations of total cholesterol (>300 to 600 mg/dL) and LDL-cholesterol (250 to 500 mg/dL) than do those with the homozygous form. Premature CHD and tendon xanthomas are characteristic clinical findings. Treatment of Familial Hypercholesterolemia Treatment requires a low-fat (<20% of total calories), low cholesterol (<100 mg/day) diet in combination with drug therapy. Usually, patients with familial hypercholesterolemia require multiple agents to lower cholesterol levels to the target range. Familial Combined Hyperlipoproteinemia Familial combined hyperlipoproteinemia (FCHL) is an autosomal dominant polygenic disorder that affects 1% to 2% of the population. Factors such as diet, glucose intolerance, and medications can influence the phenotypic presentation Familial Combined Hyperlipoproteinemia There are no definitive diagnostic tests, but family screening can help confirm the diagnosis. The phenotype of FCHL is variable, with individuals displaying high LDL-cholesterol, high VLDL-triglyceride, or both based on the genetic defect and environmental factors. Familial Combined Hyperlipoproteinemia Affected individuals require a low-fat, low-cholesterol diet plus multiple lipid-lowering drugs to achieve target goals. Fibric acid derivatives, which hydrolyze the triglyceride core of VLDL particles and increase LDL production, are recommended for treatment of the hypertriglyceridemia. Patients with FCHL often additionally require a statin or niacin to lower their LDLcholesterol level. Familial Dysbetalipoproteinemia Apo E on the surface of lipoprotein particles binds LDL receptors and facilitates clearance of remnant particles from the circulation. In individuals who are homozygous for apo E2, LPL hydrolyzes the triglyceride core and the resulting cholesterol-rich chylomicrons. VLDL and IDL remnant particles accumulate in the circulation Familial Dysbetalipoproteinemia The apoE2 allele, which has a cysteine at position 158 instead of an arginine, is the cause of FDBL when present on both alleles. ApoE2 has a lower affinity for the LDL receptor; therefore, chylomicron remnants and IDL containing apoE2 are removed from plasma at a slower rate, leading to their accumulation in blood. Familial Dysbetalipoproteinemia NOTICE: The apoE4 allele, which has an arginine instead of a cysteine at position 112, is widely known for being the major genetic risk factor for Alzheimer’s disease. It is associated with slightly higher LDL-C levels and increased ASCVD risk but is not associated with FDBL. Familial Dysbetalipoproteinemia Premature CHD, peripheral vascular disease, and xanthomas involving the palmer crease are characteristic clinical features. Individuals with familial dysbetalipoproteinemia have elevated levels of total cholesterol (300 to 400 mg/dL) and triglycerides (300 to 400 mg/dL). Familial Dysbetalipoproteinemia The definitive diagnosis of FDBL can be made either by the documentation of very high levels of remnant lipoproteins or by identification of the apoE2/E2 genotype. A variety of methods are used to identify remnant lipoproteins in the plasma, including “β-quantification” by ultracentrifugation (ratio of directly measured VLDL cholesterol to total plasma TG >0.30), lipoprotein electrophoresis (broad β band), or nuclear magnetic resonance lipoprotein profiling. Familial Dysbetalipoproteinemia Ultracentrifugation: Familial Dysbetalipoproteinemia The Friedewald formula for calculation of LDL-C is not valid in FDBL because the VLDL particles are depleted in TG and enriched in cholesterol. The plasma levels of LDL-C are actually low in this disorder due to defective metabolism of VLDL to LDL. DNA-based apoE genotyping can be performed to confirm homozygosity for apoE2, which is diagnostic for FDBL. However, absence of the apoE2/E2 genotype does not strictly rule out the diagnosis of FDBL, because other mutations in apoE can (rarely) cause this condition. Familial Dysbetalipoproteinemia Patients with FDBL usually present in adulthood with hyperlipidemia, xanthomas, or premature coronary or peripheral vascular disease. In FDBL, in contrast to other disorders of elevated TGs, the plasma levels of cholesterol and TG are often elevated to a similar degree, and the level of HDL-C is usually normal. Two distinctive types of xanthomas, tuberoeruptive and palmar, are seen in FDBL patients. Tuberoeruptive xanthomas begin as clusters of small papules on the elbows, knees, or buttocks and can grow to the size of small grapes. Palmar xanthomas (alternatively called xanthomata striata palmaris) are orange-yellow discolorations of the creases in the palms and wrists. Both of these xanthoma types are virtually pathognomonic for FDBL. Subjects with FDBL have premature ASCVD and tend to have more peripheral vascular disease than is typically seen in FH. Familial Dysbetalipoproteinemia Treatment of coexisting conditions such as diabetes and hypothyroidism can normalize lipid levels in apo E2 homozygotes. Statins are the first line in management. In the event of statin intolerance or insufficient control of hyperlipidemia, cholesterol absorption inhibitors, PCSK9 inhibitors, and fibrates are also effective in the treatment of FDBL NOTICE If the TG levels are persistently severely elevated, especially if they are >1000 mg/dL, and the total cholesterol-to-TG ratio is >8, FCS should be considered, and genetic testing of an FCS gene panel may be indicated. Reference: Harrison 2022 Familial Hypertriglyceridemia Familial hypertriglyceridemia is an autosomal dominant disorder that is characterized by overproduction of hepatic VLDL. The exact defect or mutation is unknown. Secondary factors that increase VLDL, such as diabetes, alcohol ingestion, and estrogen therapy, appear to exacerbate this condition. Familial Hypertriglyceridemia Low HDL associated with familial hypertriglyceridemia is related to increased catabolism. Individuals with this condition have hypertriglyceridemia (200 to 500 mg/dL) and low HDL-cholesterol (<35 mg/dL) at presentation. This diagnosis is considered in individuals who have a family and personal history of hypertriglyceridemia, CHD, and normal LDL levels. Cloudy infranatant after overnight refrigeration of plasma identifies a disorder of VLDL metabolism. Familial Hypertriglyceridemia Treatment starts with management of secondary factors that may exacerbate the condition. Dietary fat restriction (<10% of calories) and drug therapy with fish oil, niacin, and fibric acid derivatives should be initiated if target goals are not achieved. Familial Chylomicronemia Mutations in the LPL gene resulting in deficiency of LPL synthesis or function lead to increased circulating chylomicron and VLDL particles and severe hypertriglyceridemia. Homozygous LPL deficiency is rare. It manifests in childhood with triglyceride levels higher than 1000 mg/dL. Heterozygous LPL deficiency occurs in 2% to 4% of the population and usually requires a precipitating factor, such as uncontrolled diabetes or estrogen therapy, to manifest the phenotype. These individuals have moderate hypertriglyceridemia (250 to 750 mg/dL) that can increase to levels greater than 1000 mg/dL with secondary factors. Familial Chylomicronemia This can result in the chylomicronemia syndrome, which is characterized by marked hypertriglyceridemia (>1000 to 2000 mg/dL), pancreatitis, eruptive xanthomas, lipemia retinalis, and hepatosplenomegaly. Visual inspection demonstrates lipemic plasma. After refrigeration for 12 hours, a creamy top layer (increased chylomicrons) or turbid plasma infranatant (increased VLDL), or both, can be demonstrated. Documentation of diminished LPL activity confirms the diagnosis. Familial Chylomicronemia A diet low in fat (<10% of total calories or 20 to 25 g/day) is the primary treatment. Secondary factors such as uncontrolled diabetes and alcohol use should be addressed, and VLDL-lowering agents (e.g., fibric acid derivatives, niacin) may be needed to prevent severe hypertriglyceridemia. Apolipoprotein C-II Deficiency Apo C-II is an activating cofactor for LPL. Deficiency of apo C-II is a rare autosomal recessive disorder that leads to increased chylomicrons and VLDL particles in the circulation, resulting in severe hypertriglyceridemia. Clinical manifestations are similar to those of LPL deficiency, including hypertriglyceridemia (>1000 mg/dL) and symptoms of pancreatitis, eruptive xanthomas, lipemia retinalis, and hepatosplenomegaly. Apolipoprotein C-II Deficiency Treatment recommendations include appropriate management of secondary factors such as diabetes and hypothyroidism, dietary fat restriction (<10% of calories), and drug therapy (e.g., fibric acid derivatives). For severe hypertriglyceridemia, plasma transfusion (with apo C-II) can be considered. Xanthoma Xanthomas are lesions characterized by accumulations of lipid-laden macrophages. Xanthomas can develop in the setting of altered systemic lipid metabolism or as a result of local cell dysfunction. Thank you for your attention