Dyslipidemia

Dyslipidemia is an increase in plasma cholesterol and/or a decrease in triglyceride or HDL levels, which contributes to the development of atherosclerosis. Dyslipidemia can be primary (genetically determined) or secondary. The diagnosis is established by measuring the levels of total cholesterol, triglycerides, and lipoproteins in the blood plasma. Dyslipidemia is treated based on a specific diet, exercise, and lipid-lowering medications.

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Causes dyslipidemias

Dyslipidemia has primary causes - single or multiple genetic mutations, resulting in patients having overproduction or defects in the release of triglycerides and LDL cholesterol or underproduction or excessive release of HDL cholesterol. Primary lipid disorders are suspected in patients with clinical features of such a condition as dyslipidemia, early development of systemic atherosclerosis and coronary heart disease (before age 60 years), family history of coronary heart disease, or established serum cholesterol level > 240 mg/dL (> 6.2 mmol/L). Primary disorders are the most common cause in childhood and in a small percentage of cases in adults. Many names still reflect the old nomenclature, according to which lipoproteins were divided into a and b chains by electrophoretic separation in a gel.

Dyslipidemia in adults most often develops due to secondary causes. The most important factors for its development in developed countries are a sedentary lifestyle, overeating, especially the abuse of fatty foods containing saturated fats, cholesterol, and trans fatty acids (TFA). TFA are polyunsaturated fatty acids to which hydrogen atoms have been added; they are the most widely used in the processing of food and are an atherogenic, saturated fat. Other common secondary causes include diabetes mellitus, alcohol abuse, chronic renal failure or complete loss of renal function, hypothyroidism, primary biliary cirrhosis and other cholestatic liver diseases, drug-induced pathology (such drugs as thiazides, blockers, retinoids, highly active antiretroviral drugs, estrogen and progesterone, and glucocorticoids).

Dyslipidemia often develops in the setting of diabetes mellitus, as patients with diabetes have a tendency to atherogenesis in combination with hypertriglyceridemia and high LDL levels with simultaneously low levels of HDL fractions (diabetic dyslipidemia, hypertriglyceridemia, hyperapo B). Patients with type 2 diabetes mellitus are at particularly high risk of developing a condition such as dyslipidemia. Clinical combinations may include severe obesity and/or poor diabetes control, which may result in increased circulation of FFA in the blood, leading to increased production of VLDL in the liver. VLDL-rich triglycerides then transfer these TGs and cholesterol to LDL and HDL, helping to form TG-rich, small, low-density LDL, and remove TG-rich HDL. Diabetic dyslipidemia is often exacerbated by a significant excess of daily caloric intake and a decrease in physical activity, which are characteristic features of the lifestyle of patients with type 2 diabetes. Women with type 2 diabetes may have a specific risk of developing cardiovascular disease.

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Pathogenesis

There is no natural division between normal and abnormal lipid levels because measuring lipids is a long-term process. There is a linear relationship between blood lipid levels and cardiovascular risk, so many people with “normal” cholesterol levels strive to lower them even further. Consequently, there is no specific numerical range of levels that indicate a condition called dyslipidemia; this term is applied to those blood lipid levels that are amenable to further therapeutic correction.

The evidence for the benefit of such adjustment is strong for mildly elevated LDL levels and weaker for the task of lowering elevated triglyceride levels and increasing low HDL levels, partly because elevated triglyceride levels and low HDL levels are stronger risk factors for cardiovascular disease in women than in men.

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Symptoms dyslipidemias

Dyslipidemia itself has no symptoms of its own, but it can lead to the development of clinical symptoms of cardiovascular pathology, including coronary heart disease and obliterating atherosclerosis of the lower extremity vessels. High triglyceride levels [> 1000 mg/dL (> 11.3 mmol/L)] can cause the development of acute pancreatitis.

High LDL levels may result in eyelid xanthomatosis, corneal opacification, and tendinous xanthomas found in the Achilles, elbow, and patellar tendons and around the metacarpophalangeal joints. Homozygous patients with familial hypercholesterolemia may also have additional clinical features in the form of plantar or cutaneous xanthomas. Patients with markedly elevated triglyceride levels may have xanthomatous lesions on the trunk, back, elbows, buttocks, knees, forearms, and feet. Patients with the relatively rare dysbetalipoproteinemia may have palmar and plantar xanthomas.

Severe hypertriglyceridemia [>2000 mg/dL (>22.6 mmol/L)] may result in the appearance of white, creamy deposits in the retinal arteries and veins (lipemia retinalis). A sudden increase in blood lipids is also clinically manifested by the appearance of white, “milky” inclusions in the blood plasma.

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Forms

Dyslipidemia is traditionally classified according to the pattern of lipid and lipoprotein size increase (Fredrickson classification). Dyslipidemia is divided into primary and secondary and is subdivided depending on the increase of cholesterol only (pure or isolated hypercholesterolemia) or depending on the increase of both cholesterol and triglycerides (mixed or combined hyperlipidemia). The above classification system does not address specific lipoprotein abnormalities (e.g., decreased HDL or increased LDL), which may lead to a nosological disease despite normal plasma cholesterol and triglyceride levels.

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Diagnostics dyslipidemias

Dyslipidemia is diagnosed by measuring serum lipids, although this may not be necessary because patients have a characteristic clinical picture. Routine measurements (lipid profile) include total cholesterol (TC), triglycerides, HDL, and LDL.

Direct measurement of total cholesterol, triglycerides and HDL in blood plasma is performed; quantitative values of total cholesterol and triglyceride levels reflect the content of cholesterol and TG in all circulating lipoproteins, including chylomicrons, VLDL, LDLP, LDL and HDL. The level of fluctuation of TC values is approximately 10%, and TG - up to 25% with daily measurement even in the absence of a nosological form of the disease. TC and HDL can be measured without fasting, but in most patients, the study should be performed strictly on an empty stomach to obtain the most accurate results.

All measurements should be performed in healthy patients (outside acute inflammatory diseases), since in conditions of acute inflammation, triglyceride levels increase and cholesterol levels decrease. The lipid spectrum remains reliable during the first 24 hours after the development of acute MI, and then changes occur.

The most commonly measured LDL is the amount of cholesterol not contained in HDL and VLDL; VLDL is calculated from the triglyceride content (TG/5), i.e. LDL = TC [HDL + (TG/5)] (Friedland formula). VLDL cholesterol is calculated from the triglyceride level (TG/5) because the cholesterol concentration in VLDL particles is usually 1/5 of the total lipid content of that particle. This calculation is only valid when triglycerides are < 400 mg/dL and the patient is fasting, because food intake increases triglyceride levels in the blood. LDL can be calculated by measuring the cholesterol contained in LDL and apolipoproteins (omitting HDL and chylomicrons).

LDL-C can also be measured directly in blood using plasma ultracentrifugation, which separates the chylomicron and VLDL fractions from HDL and LDL, and by enzyme immunoassay. Direct measurement in plasma may be useful in some patients with elevated triglycerides to determine whether LDL-C is also elevated, but such direct testing is not routine in clinical practice. The role of apo B is under study because its levels reflect total non-HDL-cholesterol (i.e., cholesterol contained in VLDL, VLDL remnants, IDL, and LDL) and may be better predictors of CHD risk than LDL alone.

Fasting lipid profile should be determined in all adults >20 years and repeated every 5 years thereafter. Lipid measurement should be supplemented by determination of the presence of other cardiovascular risk factors such as diabetes mellitus, tobacco smoking, arterial hypertension and family history of coronary heart disease in first-degree relatives of men up to age 55 years or in first-degree relatives of women up to age 65 years.

There is no specific age at which patients no longer need further screening, but there is clearly no need for screening once patients reach 80 years of age, especially if they develop coronary artery disease.

Screening is indicated for patients under 20 years of age with risk factors for atherosclerosis, such as diabetes, hypertension, smoking, and obesity, a family history of coronary heart disease in close relatives, grandparents, or siblings, or a family history of cholesterol levels greater than 240 mg/dL (> 6.2 mmol/L), or dyslipidemia. If family history information is not available, as in adoption cases, screening is performed at the discretion of the treating physician.

In patients with inherited forms of coronary artery disease and normal (or near-normal) lipid levels, in patients with a strong family history of cardiovascular disease, or in patients with high LDL levels refractory to drug therapy, apolipoprotein [Lp(a)] levels should still be measured. Lp(a) levels can also be measured directly in plasma in patients with borderline high LDL levels to help guide drug therapy. C-reactive protein and homocysteine levels can also be measured in these patients.

Laboratory methods for investigating secondary causes that provoke a condition such as dyslipidemia, including determination of fasting blood glucose, liver enzymes, creatinine, TSH levels and urine proteins, should be implemented in most patients with newly diagnosed dyslipidemia and in cases of unexplained negative dynamics of individual components of the lipidogram.

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Treatment dyslipidemias

Dyslipidemia is treated by prescribing it to all patients with coronary heart disease (secondary prevention) and in some cases to patients without coronary heart disease (primary prevention). The guidelines developed by the Atherosclerosis Treatment in Adults (ATP III) Commission, acting within the framework of the National Cardiovascular Education Program (NCEP), are the most authoritative scientific and practical publication that directly defines indications for prescribing therapy to adult patients. The guidelines recommend reducing elevated LDL levels and implementing secondary prevention aimed at treating high TG levels, low HDL levels, and metabolic syndrome. An alternative treatment guideline (Sheffield table) uses the TC:HDL ratio in combination with verification of coronary heart disease risk factors for the prevention of cardiovascular risk, but this approach does not lead to the desired effect of preventive treatment.

Treatment tactics for children have not been developed. Strictly adhering to a specific diet in childhood is a difficult task, and there is no reliable scientific data indicating that lowering lipid levels in childhood is an effective method for preventing cardiovascular pathology in these same patients in the future. In addition, the issue of prescribing hypolipidemic therapy and its effectiveness over a long period of time (years) is quite debatable. And yet, the American Academy of Pediatrics (AAP) recommends such therapy in some children with elevated LDL levels.

The specific treatment regimen depends on the lipid abnormality identified, although mixed lipid abnormalities are common. In some patients, single lipid abnormalities may require a multimodality approach, while in others, a single treatment may be effective for several lipid abnormalities. Treatment should always include treatment of hypertension and diabetes, smoking cessation, and, in patients with a 10-year risk of MI or cardiovascular death of 10% or greater (as assessed by the Framingham Table, Tables 1596 and 1597), mandatory low-dose aspirin.

In general, treatment regimens are the same for both sexes.

Elevated LDL levels

The ATP III guideline recommends treatment in adults with elevated LDL-C levels and a history of CHD.

The clinical conditions that classify a patient as at risk for future cardiac events are similar to those that classify a patient as having coronary artery disease (CAD equivalents such as diabetes mellitus, abdominal aortic aneurysm, peripheral vascular occlusive disease, and symptomatic carotid artery disease); or the presence of 2 coronary artery risk factors. The ATP III guidelines recommend that such patients have an LDL-C level of less than 100 mg/dL, but it is clear that in practice the goal is even more stringent - to keep the LDL-C level less than 70 mg/dL - which is optimal for patients with very high risk (eg, those with established coronary artery disease and diabetes and other poorly controlled risk factors, or those with metabolic syndrome or acute coronary syndrome). When prescribing drug therapy, it is desirable that the dose of drugs ensures a reduction in LDL levels by at least 30-40%.

The AAP recommends dietary therapy for children with LDL-C levels greater than 110 mg/dL. Drug therapy is recommended for children aged 10 years and older who have had a poor response to dietary therapy and persistent LDL-C levels of 190 mg/dL or greater and who do not have a family history of hereditary cardiovascular disease. Drug therapy is also recommended for children aged 10 years and older with LDL-C levels of 160 mg/dL or greater and a family history of cardiovascular disease or who have 2 or more risk factors for the development of this disease. Risk factors in childhood, in addition to family history and diabetes, include smoking, hypertension, low HDL-C levels (< 35 mg/dL), obesity, and physical inactivity.

Therapeutic approaches include lifestyle changes (including diet and exercise), medications, nutritional supplements, physical therapy, other treatments, and experimental therapies. Many of these are also effective in treating other lipid disorders. Adequate physical activity has a direct effect on lowering LDL levels in some patients, which is also helpful for ideal weight control.

Changes in habitual diet and nutritional patterns and physical activity should in any case be considered the initial elements of therapy, no matter when it is carried out.

The therapeutic diet includes reducing saturated fat and cholesterol in the diet; increasing monounsaturated fat, dietary fiber, and total carbohydrates; and achieving ideal body weight. Consultation with a dietitian is often very helpful for this purpose, especially in elderly patients who have dyslipidemia.

The duration of the period of lifestyle modification before starting lipid-lowering therapy is controversial. In patients with moderate to low cardiovascular risk, 3 to 6 months is prudent. Usually, 2 to 3 visits to the doctor over 2 to 3 months are sufficient to assess motivation and determine the degree of patient adherence to the established dietary framework.

Drug therapy is the next step used when lifestyle modification alone is ineffective. However, for patients with significantly elevated LDL [>200 mg/dL (>5.2 mmol/L)] and high cardiovascular risk, drug therapy should be combined with diet and exercise from the outset of treatment.

Statins are the drugs of choice for LDL level correction; they have been shown to reduce the risk of cardiovascular mortality. Statins inhibit hydroxymethylglutaryl CoA reductase, a key enzyme in cholesterol synthesis, regulating LDL receptors and increasing LDL clearance. Drugs in this group reduce LDL levels by up to 60% and cause a slight increase in HDL and a moderate decrease in TG levels. Statins also help reduce intra-arterial and/or systemic inflammation by stimulating endothelial nitric oxide production; they can also reduce LDL deposition in endothelial macrophages and cholesterol content in cell membranes during the development of systemic chronic inflammation processes. This anti-inflammatory effect is manifested as atherogenic even in the absence of an increase in lipids. Side effects are nonspecific, but manifest themselves as an increase in liver enzymes and the development of myositis or rhabdomyolysis.

The development of muscle intoxication has been described even without an increase in enzymes. The development of side effects is more typical for elderly and senile individuals with combined polyorgan pathology and receiving multidrug therapy. In some patients, replacing one statin with another during treatment or reducing the dose of the prescribed statin eliminates all problems associated with the side effects of the drug. Muscle intoxication is most pronounced when some statins are used together with drugs that inhibit cytochrome P3A4 (for example, together with macrolide antibiotics, azole antifungal drugs, cyclosporines), and together with fibrates, especially gemfibrozil. The properties of statins are common to all drugs in the group and differ little in each specific drug, so its choice depends on the patient's condition, LDL level and the experience of medical personnel.

Bile acid sequestrants (BAS) block the reabsorption of bile acids in the small intestine, have a strong feedback regulatory effect on liver LDL receptors, promoting the capture of circulating cholesterol for bile synthesis. Drugs in this group help reduce cardiovascular mortality. To activate the reduction of LDL levels, bile acid sequestrants are usually used together with statins or nicotinic acid preparations and are the drugs of choice when prescribed to children and women planning pregnancy. These medications are a fairly effective group of lipid-lowering drugs, but their use is limited due to the side effects they cause in the form of flatulence, nausea, cramps and constipation. In addition, they can also increase the level of TG, so their use is contraindicated in patients with hypertriglyceridemia. Cholestyramine and colestipol, but not colesevelam, are incompatible (prevent absorption) with the simultaneous administration of other drugs - all known thiazides, beta-blockers, warfarin, digoxin and thyroxine - their effect can be smoothed out by prescribing FZK 4 hours before or 1 hour after their administration.

Ezetimibe inhibits intestinal absorption of cholesterol, phytosterol. It usually reduces LDL levels by only 15-20% and causes a slight increase in HDL and a moderate decrease in TG. Ezetimibe can be used as monotherapy in patients intolerant to drugs from the statin group or can be prescribed in combination with statins in patients on maximum doses of drugs of this group and having a persistent increase in LDL. Side effects are rare.

Supplementation of the treatment with a hypolipidemic diet includes the use of dietary fiber and affordable margarine containing vegetable fats (sitosterol and campesterol) or stanols. In the latter case, it is possible to achieve a maximum reduction of 10% in LDL without any effect on HDL and TG levels through competitive substitution of cholesterol on the villous epithelium of the small intestine. Addition of garlic and walnuts to the diet as food ingredients that reduce LDL levels is not recommended due to the obvious minimal effectiveness of such supplements.

Additional therapies are included in combination therapy for patients with severe hyperlipidemia (LDL < 300 mg/dL) refractory to conventional treatment, such as that seen in familial hypercholesterolemia. Therapies include LDL apheresis (in which all LDL is removed by replacement with extracorporeal plasma), ileal bypass (which blocks bile acid reabsorption), and portocaval shunting (which reduces LDL synthesis, although the mechanism is unknown). LDL apheresis is the procedure of choice in most cases where dyslipidemia has failed to achieve adequate LDL-lowering effects with optimal therapy. LDL apheresis is also typically used in patients with homozygous familial hypercholesterolemia who have had a limited or no response to drug therapy.

Among the new methods currently being developed to reduce LDL levels, the use of peroxisome proliferator-activated receptor (PPAR) agonists with thiazolidinedione-like and fibrate-like properties, LDL receptor activators, LPL activator, and recombinants of apo E are possible in the near future. Vaccination with cholesterol preparations (to induce anti-LDL antibodies and accelerate LDL clearance from serum) and transgenic engineering (gene transplantation) are conceptual areas of scientific research that are currently at the study stage, but the clinical implementation of which is possible in a few years.

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Elevated triglyceride levels

It is unclear whether elevated triglyceride levels independently influence the development of cardiovascular disease, since elevated triglycerides are associated with numerous metabolic abnormalities that contribute to coronary heart disease (eg, diabetes, metabolic syndrome). Consensus is that lowering high triglyceride levels is clinically beneficial. There are no specific therapeutic targets for correction of hypertriglyceridemia, but a triglyceride level < 150 mg/dL (1.7 mmol/L) is generally considered desirable. There are no specific guidelines for the treatment of elevated triglyceride levels in children.

Initial therapy includes lifestyle changes (moderate exercise, weight loss, and avoidance of refined sugar and alcohol). Adding 3-fatty acid-rich fish to the diet 2 to 4 times a week may be clinically effective, but the amount of 3-fatty acids in fish is often below the required level, so dietary supplements may be necessary. In patients with diabetes and dyslipidemia, blood glucose levels should be closely monitored. If these measures are ineffective, lipid-lowering drugs should be considered. Patients with very high triglyceride levels should be treated with medication from the time of diagnosis to reduce the risk of developing acute pancreatitis as quickly as possible.

Fibrates reduce triglyceride levels by approximately 50%. They begin to stimulate endothelial LPL, which leads to increased fatty acid oxidation in the liver and muscles and decreased intrahepatic VLDL synthesis. Drugs in this group also increase L-PVP by almost 20%. Fibrates can cause side effects from the gastrointestinal tract, including dyspeptic symptoms and abdominal pain. In some cases, they can cause cholelithiasis. Fibrates contribute to the development of muscle intoxication when prescribed together with statins and potentiate the effects of warfarin.

The use of nicotinic acid preparations may also have a positive clinical effect.

Statins can be used in patients with triglycerides < 500 mg/dL if there is also an increase in LDL; they can lower both LDL and TG, but still VLDL. Fibrates are the drugs of choice only if the patient has high triglycerides and dyslipidemia.

Omega-3 fatty acids in high doses [1-6 g/day eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] may have a beneficial effect on lowering triglyceride levels. EPA and DHA fatty acids are found as active ingredients in fish oil or 3-hydroxyethyl starch capsules. Side effects include belching and diarrhea and can be reduced by dividing the daily dose of fish oil capsules into 2 or 3 times daily with meals. 3-hydroxyethyl starch supplements may also be useful in the treatment of other medical conditions.

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Low HDL

Treatments aimed at increasing HDL levels may reduce the risk of death, but the literature on this topic is limited. The ATP III guidelines define low HDL levels as < 40 mg/dL (< 1.04 mmol/L); the guidelines do not specify therapeutic targets for HDL levels and recommend that medical interventions aimed at raising HDL levels be performed only after LDL targets have been achieved. Treatment of elevated LDL and TG levels often normalizes HDL levels, so that sometimes all 3 targets can be achieved simultaneously. There are no official recommendations for the treatment of low HDL levels in children.

Treatment options include increasing exercise and adding monounsaturated fats to the diet. Alcohol increases HDL levels, but its use is not recommended as a treatment because of its many other side effects. Drug therapy is recommended when lifestyle changes alone are insufficient to achieve goals.

Nicotinic acid (niacin) is the most effective drug for increasing HDL. Its mechanism of action is unknown, but it both increases HDL and inhibits HDL clearance and may promote cholesterol mobilization from macrophages. Niacin also lowers TG and, at doses of 1500 to 2000 mg/day, lowers LDL. Niacin causes flushing (and associated skin redness), pruritus, and nausea; pretreatment with low-dose aspirin may prevent these side effects, and the slow action of small divided doses often results in a significant reduction in side effects. Niacin may cause elevations of liver enzymes and, rarely, liver failure, insulin resistance, hyperuricemia, and gout. It may also increase homocysteine levels. In patients with average LDL levels and below average HDL levels, treatment with niacin in combination with statins may be very effective in preventing cardiovascular disease.

Fibrates increase HDL levels. Infusions of recombinant HDL (eg, apolipoprotein A1 Milano, a special HDL variant in which the amino acid cysteine is replaced by arginine at position 173, allowing the formation of a dimer) are currently a promising treatment for atherosclerosis, but require further development. Torcetrapib, a CETP inhibitor, significantly increases HDL and reduces LDL levels, but its efficacy in atherosclerosis has not been proven and this drug also requires further study.

Elevated lipoprotein(a) levels

The upper limit of normal for lipoprotein(a) is about 30 mg/dL (0.8 mmol/L), but individual values in African and American populations are higher. There are currently few medications that can treat elevated lipoprotein(a) levels or that have demonstrated clinical efficacy in doing so. Niacin is the only drug that directly lowers lipoprotein(a) levels; when given in high doses, it can lower lipoprotein(a) levels by about 20%. The usual treatment strategy for patients with elevated lipoprotein(a) levels is aggressive LDL-lowering.

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How is secondary dyslipidemia treated?

Diabetic dyslipidemia is treated with lifestyle changes in combination with statins to lower LDL and/or fibrates to lower TG. Metformin lowers TG, which may be the reason it is the preferred choice of antihyperglycemic agents when treating a patient with diabetes. Some thiazolidinediones (TZDs) increase both HDL and LDL (probably to a lesser extent the atherogenic ones). Some TZDs also lower TG. These drugs should not be the primary lipid-lowering agents for the treatment of lipid disorders in patients with diabetes, but they may be useful as adjunctive therapy. Patients with very high TG levels and suboptimal diabetes control may respond better to insulin than to oral hypoglycemic agents.

Dyslipidemia in patients with hypothyroidism, renal disease and/or obstructive liver disease initially involves treatment of the underlying causes, and then of the lipid metabolism abnormalities. Altered lipid profile levels in patients with slightly reduced thyroid function (TSH level at the upper limit of normal) are normalized with hormone replacement therapy. It should be considered justified to reduce the dose or completely discontinue the drug that caused the lipid metabolism disorder.

Monitoring dyslipidemia

Lipid levels should be checked periodically after initiation of therapy. There are no data to support specific monitoring intervals, but measuring lipid levels 2–3 months after initiation or change of treatment and then 1 or 2 times per year after lipid levels have stabilized is common practice.

Although hepatotoxicity and muscle toxin accumulation are rare with statins (0.5% to 2% of all cases), baseline liver and muscle enzyme measurements at the start of therapy are popular recommendations for conditions such as dyslipidemia. Many experts use at least one additional liver enzyme measurement 4 to 12 weeks after initiation of therapy and then annually during therapy. Statin therapy can be continued until liver enzymes are >3 times the upper limit of normal. Muscle enzyme levels do not need to be monitored routinely unless patients develop myalgias or other symptoms of muscle damage.

Forecast

Dyslipidemia has a variable prognosis, depending on the dynamics of the lipid spectrum and the presence of other risk factors for cardiovascular pathology.

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