Hypertriglyceridemia

Hypertriglyceridemia is an elevated level of triglycerides in blood plasma on an empty stomach.

• The 95th percentile for the population, as a function of age and sex, is used as the limits of the triglyceride level .
  
• Hypertriglyceridemia may be accompanied by quantitative or qualitative impairments from the side of lipoproteins , the level and ratio of which may also vary significantly.
  
• Indicators of triglycerides in different states may be subject to significant fluctuations : an adequate metabolic stress with moderate hypertriglyceridemia can go to severe.
  
• Increased plasma triglyceride concentration increases the risk of developing cardiovascular disease as an independent factor and in conjunction with other associated risk factors, such as obesity, metabolic syndrome, diabetes mellitus, elevated levels of pro-inflammatory and pre-thrombotic biomarkers.
  
• If there is an increase in triglyceride levels (especially> 10 mmol / l), there is also a risk of developing acute pancreatitis .
  
  The main sources of triglycerides in the blood plasma can be divided into:
  
•  Endogenous (from the liver) - triglycerides come in the composition of particles containing very low density lipoproteins (VLDL)
  
•  exogenous (food fats) - triglycerides come in the composition of chylomicrons
  
  When lipoproteins and chylomicrons enter the fat or muscle tissue from the capillaries under the influence of lipoprotein lipase, their hydrolysis to free fatty acids takes place.After eating, more than 90% of triglycerides circulating in the blood plasma come from the gastrointestinal tract as part of chylomicrons, while during limited eating, endogenous triglycerides are secreted by the liver and predominate in VLDL.
  
  Thus, an increase in triglyceride levels in plasma occurs:
  
• as a result of their increased education in the gastrointestinal tract or liver or
  
• due to a decrease in the processes of peripheral catabolism of fats (mainly as a result of a decrease in the lipoprotein activity of lipase)Classification of hypertriglyceridemia
  
  Hypertriglyceridemia can be divided into:
  
• Primary
  
• Secondary
  
  Panel III on managing adult patients in the Canadian National Cholesterol Education Program proposed to divide triglyceride levels into four groups in the context of determining the risk of cardiovascular disease:
  
•  Normal (<1.7 mmol / L)
  
•  borderline (1.7-2.3 mmol / l)
  
•  high (2.3-5.6 mmol / l)
  
•  very high (> 5.6 mmol / l)
  
  Also there is the classification of Donald Fredrickson , adopted by the World Health Organization as an international standard nomenclature of hyperlipidemia.However, this classification does not take into account the level of high-density lipoprotein (HDL), which is an important factor that reduces the risk of atherosclerosis, as well as the role of genes that cause lipid disorders.For these reasons, it is sometimes considered obsolete.
  
  Primary hypertriglyceridemia
  Triglycerides are excreted from the composition of chylomicrons in tissues (except the liver) by hydrolysis of the lipoprotein lipase system with the co-factor apolipoprotein (Apo) C-II.
  Hereditary chylomicronemia (type I hyperlipoproteinemia) and primary mixed hyperlipidemia (V type) are characterized by the pathological appearance of chylomicrons after a 12-14 hour meal restriction.A peculiarity of clinical manifestations observed in hereditary chylomicronemia and primary mixed hyperlipidemia is the appearance of xanthomas, retinal lipemia, hepatosplenomegaly, symptoms of the central nervous system, such as irritability, recurrent epigastric pain with an increased risk of acute pancreatitis.In samples of lipemic plasma after night cooling, a thick layer emerges on the surface.And with hereditary chylomicronemia, and with mixed hyperlipidemia, fasting plasma levels determine triglyceride levels higher than 10 mmol / l.With hereditary chylomicronemia, clinical symptoms appear in childhood and are accompanied by a deficiency of lipoprotein lipase, a decrease in Apo-CII activity, and homozygous gene mutations.In primary mixed hyperlipidemia with infrequent gene mutations, symptoms appear in adulthood with a less severe functional deficit and significantly increased total cholesterol than with hereditary chylomicronemia.The prevalence of hereditary chylomicraemia in the population in comparison with primary mixed hyperlipidemia is lower (about 1 per 10 million and 1 per 10,000, respectively).With familial chylomicrahemia during the biochemical analysis, plasma lipoprotein lipase activity taken after intravenous heparin is decreased, but this test is not performed in all laboratories.Hereditary hypertriglyceridemia (type IV hyperlipoproteinemia) is determined solely by an increase in VLDL level, which contain much less triglycerides than chylomicra.The prevalence of this disorder in the population is about 5-10%.Typically, there is a moderate increase in plasma triglycerides (3-10 mmol / L), often with low HDL.Hereditary hypertriglyceridemia is directly associated with an increased risk of developing cardiovascular diseases, obesity, insulin resistance, diabetes mellitus, hypertension and hyperuricemia.A combined group of hereditary diseases combines combined hyperlipoproteinemia (type IIb) with an autosomal dominant type of inheritance at variable penetrance .The prevalence of these diseases in the population is 2-5%.The main distinguishing feature of this group of diseases is the increase in the fraction of VLDL and low-density lipoprotein (LDL) with a decrease in HDL.These changes are related to inheritance, at least from one relative of the first degree of kinship, who have determined similar violations of the lipid profile.It is assumed that the disorders are transmitted through the heterozygote at random, changing the activity of lipoprotein lipase, or by mutations of the APOC3 gene, but the molecular basis underlying the combined hereditary hyperlipoproteinemia is usually not detectable.Recently, a USF1 gene has been identified that can encode a triggering factor, but other genes, including APOA5 and APOC3, can sometimes play a role in the development of these disorders.There is also a hereditary disbetalipoproteinemia (type III hyperlipoproteinemia) , the population prevalence of which is about 1-2 cases per 20 thousand of the population.The main symptom of the disease is an increase in the level of triglyceride-rich lipoprotein residues, known as medium-density lipoprotein (LPSP) or -LVPP, which lead to an equimolar increase in the level of total cholesterol and triglycerides in the blood plasma.People with this disorder are most often homozygous for the defective isoform APOE E2, in which arginine is replaced by cysteine, which distinguishes it from the E3 isoform in residue 158. Phenotypic expression, however, usually requires co-factors such as obesity, type 2 diabetes, or hypothyroidism.The plasma LDL level is reduced due to a VLDL metabolism impairment .The increase in cholesterol (cholesterol) of VLDL is determined, while the diagnostic test is the ratio of TG and E2 / E2 homozygotes.Patients with these diseases often have an increased risk of developing cardiovascular diseases.A characteristic clinical manifestation of disorders are bumpy xanthomas or eruptions on the extensor elbow surfaces of the extremities and are flat in the region of the palmar fold.
  
  Secondary hypertriglyceridemia
  Some conditions associated with metabolic disorders are often associated with an elevated level of triglycerides.This may mean that individuals with secondary hypertriglyceridemia may be assessed minor hereditary metabolic defects.Obesity is the most common metabolic stress factor associated with hypertriglyceridemia .A similar connection was found with poorly controlled diabetes mellitus type 2 and excessive consumption of alcoholic beverages.
  
  Obesity, metabolic syndrome, diabetes mellitus
  People who have an increased content of visceral adipose tissue have an elevated triglyceride level and a lower level of HDL cholesterol.Approximately 80% of men with a waist circumference> 90 cm and a plasma triglyceride level of 2 mmol / L are characterized by a metabolic triad of non-traditional markers of cardiovascular diseases :
  
• Hyperinsulinemia
  
• Increased levels of Apo-B
  
• LDL
  This triad can increase the risk of developing cardiovascular diseases by 20 times .With type 2 diabetes, there is a deterioration in the ability of glucose uptake by tissues due to insulin and there are no adequate mechanisms for replacing this process.In addition, among people without type 2 diabetes, but with insulin resistance, hyperinsulinemia is associated with a number of metabolic disorders called MS.This syndrome is often observed in patients with obesity of central genesis and is a serious risk factor for the development of type 2 diabetes.It is characterized by the presence of glucose tolerance, dyslipidemia (triglycerides> 1.7 mmol / L and low HDL cholesterol) and arterial hypertension.In metabolic syndrome and diabetes, hypertriglyceridemia manifests itself:
  
• Increased VLDL level in blood plasma with / without chylomicronemia
  
• a decrease in lipoprotein lipase activity and an increase in the activity of proteins responsible for cholesterol transport
  
• increased release and metabolism of free fatty acids
  Clinically, obesity of the liver is often observed in such patients.
  
  Alcohol
  With excessive consumption of alcoholic beverages, hypertriglyceridemia is associated with an increase in VLDL with / without chylomicronemia .In some cases, plasma triglycerides may remain within the normal range as a result of an adaptive increase in lipolytic activity.However, alcohol can also worsen lipolysis, especially when the patient has a functional deficiency of lipoprotein lipase, which leads to a marked increase in triglycerides.
  
  Kidney Diseases
  In nephrotic syndrome, an increase in the LDL cholesterol fraction is the main manifestation of dyslipoproteinemia, which is often accompanied by an increase in Apo-B, including VLDL.The main mechanism of increasing triglycerides is the enhancement of liver function, while also increasing the synthesis of albumin as compensation for renal protein malnutrition.Uremia is associated with an increase in VLDL, which reflects a decrease in lipolysis due to the toxic effect of uremic metabolites.
  
  Pregnancy
  During the third trimester of pregnancy, triglycerides of blood plasma often increase three times from the initial level .As a rule, such changes are physiological, do not manifest themselves clinically and disappear without a trace in normal lipoprotein lipase activity .Chylomicronemia during pregnancy is usually very rare, and its appearance may indicate a risk of developing acute pancreatitis, which can be fatal for both the mother and the fetus.
  
  Non-alcoholic steatosis of the liver
  These disorders can occur in about a third of North Americans, reflecting an increase in the incidence of obesity, insulin resistance, and metabolic syndrome.A third of patients with hypertriglyceridemia may have non-alcoholic steatohepatitis.In addition , the toxic effect of various lipid fractions, oxidative stress, cytokines and proinflammatory mediators contribute to the progression of the disease from fatty liver degeneration to non-alcoholic steatohepatitis.The main manifestations of dyslipidemia in disorders associated with non-alcoholic steatosis of the liver are an increase in the level of TG and a decrease in the level of HDL cholesterol.Small studies have shown that treating such disorders with statins is more effective than fibrates.
  
  Other states
  Hypothyroidism is usually accompanied by an increase in the level of LDL, while the level of triglycerides can also be increased.Paraproteinemia (hypergammaglobulinemia in macroglobulinemia, myeloma, lymphoma and lymphocytic leukemia) and autoimmune disorders (eg, systemic lupus erythematosus) can also cause hypertriglyceridemia, most likely by influencing lipolysis processes.
  
  Effects of drugs
  A large number of drugs can increase the concentration of triglycerides in the blood plasma .In such cases, it is necessary to consider the possibility of correcting hypertriglyceridemia.If it is impossible to reduce the dosage, change the route of administration of the drug or replace it with another class , then in the detection of violations it is necessary to appoint either a diet or drugs that lower the level of triglycerides.Patients who are prescribed antiretroviral therapy, especially protease inhibitors, often have lipodystrophy, dyslipidemia and insulin resistance.80% of them develop hypertriglyceridemia and 50% have hypercholesterolemia.With a combination of these disorders in individuals undergoing active antiretroviral therapy , the relative risk of cardiovascular disease is increased by 26%.Ritonavir and lopinavir most often cause dyslipidemia, reverse transcriptase inhibitors (stavudine, nevirapine and efavirenz) - less.Often the level of triglycerides is normalized when drugs can be temporarily discontinued or replaced by others if there is no alternative to prescribing antiretroviral therapy.
  
  Secondary causes leading to hypertriglyceridemia:
  
• Obesity
  
• Metabolic syndrome with a TG level of> 1.7 mmol / L
  
• High-calorie diet with a high content of fats and carbohydrates with a positive energy balance
  
• Insufficient physical activity
  
• Alcohol consumption
  
• Type 2 CD
  
• Diseases of the kidneys, uremia or glomerulonephritis
  
• Hypothyroidism - is often the cause of hypertriglyceridemia at a normal level of OXC.
  
• Pregnancy: a physiological increase in triglyceride levels during the third trimester
  
• Autoimmune disorder (paraproteinemia, systemic lupus erythematosus)
  Any preparation from the presented groups:
  
• corticosteroids
  
• oral estrogens
  • tamoxifen
  
• antihypertensives (non-selective-blockers, thiazides)
  
• isotretinoin
  
• bile acid resins
  
• cyclophosphamide
  
• antiretroviral drugs used in HIV infection
  
• psychotropic drugs (phenothiazines, second-generation antipsychotics)
  Second-generation antipsychotics are often associated with the development of obesity, hypertriglyceridemia, hyperglycemia, and type 2 diabetes.Clozapine and olanzapinemost strongly disrupt metabolism, aripiprazole and ziprasidone are the least, while risperidone and quetiapine have an intermediate effect.Mental disorders associated with lifestyle can also predispose to metabolic disorders.Thus, with the appointment of second-generation antipsychotics, it is necessary to regularly monitor (every 8-12 months) levels of glycemia and lipoproteins.Triglycerides and atherosclerosis
  
  Moderate hypertriglyceridemia is an independent risk factor for cardiovascular events .In the course of the PROCAM study, an increase in cardiovascular events was detected with an increase in the level of triglycerides from 2.3 mmol / l to 9.0 mmol / l after correction of other risk factors.Other studies have shown a strong relationship between plasma triglyceride levels and the likelihood of cardiovascular disease.A meta-analysis conducted over 10 years and covering several thousand patients showed that an increase in triglycerides by 1 mmol / L increased the risk of developing cardiovascular diseases by 32% in men and by 76% in women, regardless of the initial level of HDL cholesterol.
  
  Hypertriglyceridemia and acute pancreatitis
  
  In a small number of cases, but with high probability, hypertriglyceridemia increases the risk of developing acute pancreatitis .At a level of 5-10 mmol / L, the risk of developing acute pancreatitis is small, but it rises sharply at> 10 mmol / l, when triglycerides are mainly represented by chylomicra.The risk of developing at a triglyceride concentration is 1000 mg / dL (about 11.3 mmol / L), but the clinic uses a rounded figure of 10 mmol / l, which indicates a very high level of triglycerides.The ability of the pancreas to produce lipase explains the association of acute pancreatitis with elevated triglyceride levels.Disruption of lipoprotein metabolism is often detected even before the diagnosis of acute pancreatitis associated with hypertriglyceridemia.The risk of developing acute pancreatitis increases with any factor in which the triglyceride level may exceed 10 mmol / l.Acute pancreatitis associated with hypertriglyceridemia is often preceded by episodic nausea and epigastric pain, in which the amylase is within normal limits according to the serological testimony. Diagnosis can also suggest such symptoms as the presence of xanthoma or retinal lipemia. Diet with restriction of edible fats or use of fibratescan prevent the development of acute pancreatitis. Treatment of acute pancreatitis includes: stabilization of hemodynamic parameters, administration of parenteral nutrition, nasogastric intubation and normalization of metabolic parameters. The decrease in the level of triglycerides of blood plasma is inherently associated with the restriction of high-calorie food. The appointment of plasmapheresis is not always effective, so it is used very rarely. In different people, the threshold of triglycerides for the development of acute pancreatitis may be very different, in some patients the symptoms of the disease are absent at a constant level of triglycerides> 40 mmol / l. 
  Non-drug treatment 
  
  Treatment should include: 
  
• Weight reduction 
  
• Diet adjustment 
  
• Physical exercise 
  
  Diet correction should focus on: 
  
• reduction in weight 
  
• total caloric intake of food 
  
• consumption of fats and pure carbohydrates (ie foods with a high glycemic index). 
  
  Drinking alcoholic drinks should be limited. 
  
  In cases of severe hyperchylomicronemia, it is recommended: 
  
• to reduce the intake of fats in the total food volume to 10-15% (approximately 15-20 g / day) with the restriction of saturated, unsaturated and combination fats. 
  
• consultation of a dietitian. 
  
  In cases of moderate hypertriglyceridemia, triglycerides: 
  
• limiting intake of saturated and combined fats 
  
• increasing aerobic activity 
  
  According to the Canadian National Cholesterol Education Program: 
  
• the intake of carbohydrates in the diets should be 55-60% 
  
• the intake of proteins in the daily ration should be 15-20% 
  
• the consumption of fats, including saturated ones, should not exceed 30 and 7%, respectively. 
  Approximately 25% triglycerides as a result of diet and weight reduction. 
  
  Omega-3 fatty acids(eicosapentaenoic and docosahexaenoic acids) are components of the Mediterranean diet, which includes a large number of seafood. The daily intake of 4 grams of omega-3 fatty acids, along with the restriction of total calorie content and the consumption of saturated fats, can reduce the level of TG by 20%. However, if other recommendations are not followed, the use of only omega-3 fatty acids is ineffective. 
  Drug therapy to reduce the risk of cardiovascular disease 
  
  
• Drug treatment of hypertriglyceridemia must start with a single drug in combination with a dietary correction.
• The appointment of two drugs and more is performed with severe hypertriglyceridemia and resistance to monotherapy and a diet under the control of creatinine, creatine kinase and transaminases.
  
  Fibrates 
  Fibrin acid derivatives: 
  
• gemfibrozil 
  
• bezafibrate 
  
• fenofibrate 
  are the basis of drug treatment for hypertriglyceridemia. 
  Fibrates can reduce the level of triglycerides in blood plasma by 50% and increase the level of HDL cholesterol by 20%. 
  As a rule, therapy with fibrates is well tolerated. Very rarely there are such side effects as hepatitis or myositis. 
  Despite the fact that fibrates are prescribed less often than statins, their use in certain cases can bring significant benefits. 
  
  Statins 
  Newer drugs from the statin group, when used at higher therapeutic dosages, can significantly reduce the level of triglycerides.
  However, they are not first-line drugs at a triglyceride level> 5 mmol / l. 
  The advantage of statins is their stronger effect on the reduction of endpoints in IHD, especially in patients with type 2 diabetes. 
  Like fibrates, statins are well tolerated, and their administration rarely causes myopathy or hepatotoxicity. 
  
  Nicotinic acid 
  Taking nicotinic acid up to 3 g / day can reduce triglycerides by 45%, increase HDL cholesterol by 25% and reduce LDL cholesterol by 20%. 
  Clinical trials have shown a reduction in cardiovascular disease in the administration of nicotinic acid.
  However, nicotinic acid often causes dizziness, skin rashes and itching. These negative effects can be minimized by starting therapy at low daily doses with its gradual increase, as well as additional administration of acetylsalicylic acid or long-acting drugs of nicotinic acid. Other less common side effects are possible, such as increased levels of hepatic enzymes, uric acid, glucose tolerance, and gastrointestinal disorders. 
  
  Other lipid-lowering agents 
  Bile acid resins increase the level of triglycerides, while inhibitors of cholesterol absorption (ezetimibe), on the contrary, are reduced. 
  
  Combination of fenofibrate and ezetimibe, according to recent studies, is safe and effective in patients with elevated triglyceride levels and LDL cholesterol. 
  Recommendations for correcting triglyceride levels 
  In 2006, the recommendations of the Canadian Working Group on Hypercholesterolemia and Dyslipidemia did not specify what level of triglycerides should be achieved. Whereas in the recommendations of the National Cholesterol Education Program, it was mentioned that at a TG level of 1.7 mmol / L, therapy should be aimed at correcting the level of LDL cholesterol in accordance with the risk of CHD in this patient.
  
  Therapy strategy in patients with elevated triglycerides : Triglyceride 
  
  level <2 mmol / l 
  Treatment : 
  • continue monitoring 
  • lipid profile should be reassessed regularly and LDL cholesterol correction should be made 
  Repeated testingin 6 - 12 months. 
  
  The level of triglycerides is 2-5 mmol / l. 
  Medical measures : 
  • (1) correction of lifestyle, reduction of fat intake, simple carbohydrates; decreased alcohol consumption; increased physical activity; it is necessary to regularly reassess the lipid profile and correct LDL cholesterol. 
  • (2) treatment of secondary factors: in case of diabetes, monitor the glycemic profile; correct treatment and prescribe drugs that do not affect the lipid profile 
  • (3) if necessary, consider pharmacological treatment: reduce the level of LDL by prescribing statins, apply omega 3-saturated acids in the form of seafood or medicinal preparations; Nicotinic acid in prolonged form 
  Repeated testingin 3-6 months. 
  
  The level of triglycerides is 5-10 mmol / l. 
  Therapeutic measures : 
  • (4) more intensively carry out the activities described in paragraphs 1 - 3, and LDL cholesterol is not assessed at a triglyceride level> 5 mmol / l; informative may be the determination of the level of Apo-B 
  • (5) nazanat therapy with fibrates: bezafibrate at 400 mg / day, fenofibrate (lipidyl micro at a dose of 200 mg / day, lipidyl supra at a dose of 160 mg / day, lipidyl EZ at 145 mg / day , gemfibrozil (lopid) for 600 - 1200 mg / day 
  Repeated testing after 2 - 3 months 
  
  Triglyceride level 10 mmol / l 
  Treatment :
  • (6) more intensively carry out the activities described in paragraphs 1 - 3; at a clinic of acute pancreatitis: low-fat diet (10-15% of fat from total calorie content of food); refusal to drink alcohol; Insulin for the normalization of blood glucose levels; hospitalization of the patient (parenteral nutrition, plasma-substitution therapy is ineffective) 
  • (7) appoint fibrate therapy under the control of blood biochemistry 
  • (8) the patient should be under constant supervision 
  Re-testing after 1 to 2 months.