The reasons for the increase in blood fat levels are a means of normalization. Primary hyperlipoproteinemia due to single gene mutation Type 2a hyperlipoproteinemia symptoms

30.12.202027.05.2017

Hyperlipoproteinemia and other lipid metabolism disorders

Hyperlipoproteinemia and other lipid metabolism disorders. Part 3

Michael E. Brown, Joseph L. Goldstein (Michael S. Brown, Joseph L. Goldstein)

Familial hypercholesterolemia.

This common autosomal dominant disorder affects about 1 in every 500 people. It is caused by a mutation in the LDL receptor gene. In heterozygotes, a two- and three-fold increase in the level of total cholesterol in plasma is found, which is considered the result of an increase in the amount of LDL. In patients with two mutant genes of the LDL receptor (familial homozygous hypercholesterolemia), the plasma LDL cholesterol content is increased 6-8 times.

Clinical manifestations. Heterozygotes with familial hypercholesterolemia can be detected already at birth, since in their umbilical cord blood the content of LDL and, consequently, total cholesterol is increased by 2-3 times. An elevated plasma LDL level persists throughout the patient's life, but symptoms usually appear only after the age of 20-30 years. The most important feature is the premature and accelerated development of coronary atherosclerosis. Myocardial infarction occurs at the age of 20-30 years, and the peak of its frequency is recorded after the age of 30-40 years. Among patients aged 60 years, approximately 85% have had myocardial infarction. In women, its frequency also increases, but the average age at the onset of its appearance in them is 10 years older than in men. Heterozygotes for this defect make up approximately 5% of all patients with myocardial infarction.

The second notable clinical manifestation of heterozygosity for this defect is tendon xanthomas. They are nodular swellings, usually along the Achilles and other tendons near the knee and elbow joints and along the back of the hand. Xanthomas are formed as a result of deposits of LDL cholesterol esters in tissue macrophages. The macrophages overflow with lipid droplets and turn into foam cells. Cholesterol is also deposited in the soft tissues of the eyelids, forming xanthelasma, and in the cornea, forming a corneal arch. If tendon xanthomas have diagnostic value in familial hypercholesterolemia, then xanthelasmas and corneal arches are also found in many healthy adults. The frequency of tendon xanthomas in familial hypercholesterolemia increases with age, and they occur in about 75% of heterozygotes for this defect. The absence of tendon xanthomas, naturally, does not exclude familial hypercholesterolemia.

About one in a million people in the population inherits both copies of the familial hypercholesterolemia gene and is homozygous for this defect. Plasma LDL cholesterol levels are significantly elevated from birth. Already in newborns, a peculiar type of palmar skin xanthomas is often determined, and by the age of 6 years. They are raised, yellow, flat formations in injured areas of the skin, such as knees, elbows, and buttocks. They almost always develop in the interdigital spaces of the hand, especially between I and II fingers. Tendon xanthomas, corneal arches and xanthelasmas are also characteristic. Atherosclerosis of the coronary arteries is often clinically manifested even before the age of 10 years, and myocardial infarction even at the age of 18 months. In addition, cholesterol deposits in the aortic valve can cause symptoms of aortic stenosis. Usually, homozygotes die of myocardial infarction before the age of 20.

In familial hypercholesterolemia, the frequency of obesity and diabetes mellitus does not increase; in patients, body weight, as a rule, is even less than normal.

Pathogenesis. The primary defect is localized in the LDL receptor gene. Experiments on cultured cells made it possible to identify at least 12 mutant alleles at this locus, which can be combined into three classes. With the most common of them, called receptor-negative, the gene product is devoid of functional activity. At the second most frequent - receptor-defective - the receptor has only 1-10% of normal binding capacity in relation to LDL. In the third, characterized by impaired internalization, a receptor is formed that binds LDL, but does not carry out the transfer of bound lipoprotein into the cell. This rare allele causes the so-called internalization defect. Homozygotes have two mutant alleles at the LDL receptor locus, and therefore their cells are completely or almost completely unable to bind or absorb LDL. In heterozygotes, the locus of the LDL receptor contains one normal and one mutant allele, so their cells can bind and absorb LDL with an intensity of about half that of normal.

Due to the decreased activity of LDL receptors, the catabolism of these lipoproteins is blocked, and their amount in plasma increases in proportion to the decrease in receptor function. In homozygotes, not only catabolism is blocked, but also LDL production increases, which is believed to be the result of the absence of LDL receptors on liver cells. The liver loses its ability to remove LDPEs from plasma at a normal rate, and as a result, more of them are converted to LDL. This overproduction of LDL, along with the ineffectiveness of their catabolism, is responsible for the high levels of this class of lipoproteins in patients. An increase in the level of LDL leads to their greater uptake by "cleaner" cells, which, accumulating in different areas, form xanthomas.

Acceleration of the atherosclerotic process in the coronary arteries in familial hypercholesterolemia is also due to high levels of LDL, which excessively infiltrate the vascular walls when the endothelium is damaged. Large amounts of LDL, which have penetrated into the interstitium of the arterial wall, are inaccessible to the "cleaner" cells, and, in the end, atherosclerosis develops. High levels of LDL can also accelerate platelet aggregation at sites of endothelial injury, thereby increasing the size of atherosclerotic plaques.

Diagnostics. Heterozygous familial hypercholesterolemia is suggested when an isolated increase in plasma cholesterol levels is detected against the background of unchanged triglyceride concentrations. An isolated increase in cholesterol levels is usually due to an increase in the concentration of only LDL (type 2a). However, most individuals with type 2a hyperlipoproteinemia do not have familial hypercholesterolemia. They have a special form of polygenic hypercholesterolemia, which occupies the upper plateau on the bell-shaped curve of the distribution of cholesterolemia values \u200b\u200bin the general population. Type 2a hyperlipoproteinemia also accompanies multiple type hyperlipidemia. In addition, it can be a symptom of a variety of metabolic disorders, including hypothyroidism and nephrotic syndrome.

Heterozygous familial hypercholesterolemia can be distinguished from persons with polygenic hypercholesterolemia and multiple lipidemia in several ways. First, in familial hypercholesterolemia, plasma cholesterol levels are usually higher. Its concentration of 3500-4000 mg / l is more likely to indicate heterozygous familial hypercholesterolemia than other anomalies. However, in many patients with heterozygous familial hypercholesterolemia, the cholesterol level is only 2850-3500 mg / l, which does not allow to exclude another pathology. Secondly, tendon xanthomas make it possible to actually cast aside doubts about the diagnosis of familial hypercholesterolemia, since they are usually absent in patients with other forms of hyperlipidemia. Third, if in doubt about the diagnosis, other family members should be examined. With familial hypercholesterolemia, half of the first-degree relatives have an elevated plasma cholesterol level. Hypercholesterolemia in relatives is especially informative if it is found in children, since an increase in cholesterol levels in childhood is pathognomonic for familial hypercholesterolemia.

In about 10% of heterozygotes for familial hypercholesterolemia, plasma triglyceride levels are simultaneously elevated (type 26). In these cases, the disease is difficult to differentiate from multiple type hyperlipidemia. Tendon xanthomas or the detection of hypercholesterolemia in children from the patient's family provide significant assistance in differential diagnosis.

Diagnosis of homozygous familial hypercholesterolemia, as a rule, does not cause difficulties if the doctor is familiar with the clinical picture of the disease. Most patients in childhood go to a dermatologist due to skin xanthomas. Sometimes a doctor is consulted only after signs of angina pectoris appear or the onset of fainting caused by xanthomatous aortic stenosis. Cholesterol levels above 6000 mg / l with normal triglyceride levels and the absence of jaundice in children is a very significant diagnostic sign. Both parents would have had elevated cholesterol levels and other signs of heterozygous familial hypercholesterolemia.

In specialized laboratories, the diagnosis of both heterozygous and homozygous familial hypercholesterolemia can be established by directly determining the number of LDL receptors on cultured skin fibroblasts or freshly isolated blood lymphocytes. Homozygous familial hypercholesterolemia is diagnosed in utero the absence of LDL receptors on cultured cells of the amniotic fluid. Mutant genes of the LDL receptor can be identified directly in the genomic DNA of the patient using restriction and so-called southern blots.

Treatment. Since atherosclerosis in this disease is caused by a prolonged increase in plasma LDL-C levels, any attempt should be made to normalize it. Patients should be placed on a diet low in cholesterol and saturated fat and high in polyunsaturated fat. This usually means eliminating milk, butter, cheese, chocolate, crabs and fatty meats from it, and adding polyunsaturated vegetable oils such as corn and sunflower. In this case, the plasma cholesterol level in heterozygotes is reduced by 10-15%.

If diet fails to normalize cholesterol, bile acid resins such as cholestyramine should be added. They trap bile acids excreted by the liver into the intestines and prevent their reabsorption. The liver responds to a decrease in the amount of bile acids by converting additional amounts of cholesterol into them. This is accompanied by an increase in the synthesis of LDL receptors in the liver, which in turn causes a decrease in plasma LDL levels. Unfortunately, ballrooms respond to a decrease in bile acids by increasing hepatic synthesis and cholesterol, ultimately limiting the long-term efficacy of bile acid sequestrants. When a diet is combined with bile acid binding resins, the plasma cholesterol level of heterozygotes is usually reduced by 15-20%. By introducing additional nicotinic acid, it is possible to reduce the compensatory increase in hepatic cholesterol synthesis and thereby further reduce its concentration in plasma. The main side effects of bile acid resins include bloating, cramping, and constipation. The main side effects of nicotinic acid are associated with its hepatotoxicity. In most patients, it also causes congestion to the head and headache. For the treatment of familial hypercholesterolemia, probucol is also used. Its mechanism of action is unknown.

Great hopes in the treatment of patients with hypercholesterolemia are associated with a new class of experimental drugs. They inhibit 3-hydroxy-3-methylglutaryl coenzyme A-reductase, one of the enzymes on the pathway of cholesterol biosynthesis. With a decrease in cholesterol synthesis, LDL production decreases and their clearance by the liver increases due to an increase in the production of LDL receptors. The combination of these effects leads to a decrease in plasma cholesterol levels by 30-50%. HMG-CoA reductase inhibitors are even more effective when administered with bile acid-binding resins (cholestyramine). One of the inhibitors (mevinolin) is in clinical trials.

Moderate or significant reductions in plasma cholesterol levels in heterozygotes often occur after intestinal anastomosis bypassing the ileum. This operation has the same effect as the resin, that is, it provokes an acceleration of the excretion of bile acids in the feces. It can be indicated for patients who cannot tolerate drug treatment.

Homozygotes are usually more difficult to treat, presumably because they cannot increase their LDL receptor production. Combined treatment (diet, bile acid binding resin and niacin) is generally ineffective. Several children have been successful with portocaval anastomosis. However, this treatment is still being tested. In all homozygotes, cholesterol levels are reduced with plasma exchange therapy administered at monthly intervals. (Blood corpuscles are separated by centrifugation.) After each plasma exchange procedure, the plasma cholesterol content decreases to about 3000 mg / l, and then gradually returns to the initial level within 4 weeks. When the necessary equipment is available, plasma exchange is the treatment of choice for homozygotes. One child had a liver transplant that produced LDL receptors and lowered LDL levels by 80%.

Familial hypertriglyceridemia.

This common autosomal dominant anomaly is accompanied by an increase in plasma VLDL levels, resulting in hypertriglyceridemia.

Clinical manifestations. Hypertriglyceridemia usually appears no earlier than in puberty or post-pubertal period. The fasting plasma triglyceride level then rises to 2000-5000 mg / L (lipoproteinemia, type 4). The triad is usually identified: obesity, hyperglycemia, and hyperinsulinemia. Hypertension and hyperuricemia are often associated.

The incidence of atherosclerosis is increasing. According to the results of one study, patients with familial hypertriglyceridemia make up 6% of all people with myocardial infarction. However, it has not been proven that hypertriglyceridemia itself contributes to atherosclerosis. As noted, diabetes, obesity and hypertension are often associated with this disease. Each of these pathologies could by itself contribute to the development of atherosclerosis. For familial hypertriglyceridemia, xanthomas are uncommon.

Mild to moderate hypertriglyceridemia can be sharply increased by a variety of provoking factors. These include uncompensated diabetes mellitus, alcohol abuse, birth control pills containing estrogens, and hypothyroidism. In each case, the plasma triglyceride level may exceed 10 g / L. During periods of exacerbation, patients develop mixed hyperlipidemia, i.e. the concentration of both VLDL and chylomicrons (lipoproteinemia, type 5) increases. A high level of chylomicrons predisposes to the formation of eruptive xanthomas and the development of pancreatitis. After elimination of the effect of passing factors, chylomicron-like particles from the plasma disappear and the concentration of triglycerides returns to the initial level.

In some patients from some families, a severe form of mixed hyperlipidemia develops even in the absence of known complicating factors. In these cases, one speaks of the so-called familial hyperlipidemia of type 5. Other members of the same family may have only a mild form of the disease with moderate hypertriglyceridemia without hyperchylomicronemia (type 4).

Pathogenesis. Familial hypertriglyceridemia is inherited as an autosomal dominant trait, which means a single gene mutation. However, the nature of the mutant gene and the mechanism by which it causes hypertriglyceridemia have not been elucidated. Probably, this disease is genetically heterogeneous, i.e., the phenotype of hypertriglyceridemia in different families can be caused by different mutations.

In some patients, the main defect seems to be a violation of the catabolism of VLDL triglycerides. With the acceleration of VLDL production due to obesity or diabetes, there is no proportional increase in their catabolism and hypertriglyceridemia develops. The reason for the disruption of catabolism is unclear. After the introduction of heparin, the activity of lipoprotein lipase in the plasma, as in normal conditions, increases, and violations of the structure of lipoproteins cannot be detected.

The increase in the incidence of diabetes and obesity in this syndrome is considered to be accidental and related to the fact that both conditions are usually accompanied by an increase in the production of VLDL and, therefore, increase hypertriglyceridemia. Family examinations reveal relatives of the patient suffering from diabetes without hypertriglyceridemia and triglyceridemia without diabetes, which indicates the independent inheritance of these diseases. With the simultaneous inheritance of genes for diabetes and hypercholesterolemia, the latter becomes more pronounced, and patients are more likely to attract the attention of doctors. Similarly, in patients with familial triglyceridemia and normal body weight, the level of triglycerides in plasma is increased to a lesser extent than when this disease is combined with obesity, so they are less likely to attract the attention of a doctor. With obesity, hypertriglyceridemia increases and the likelihood of its detection increases.

Diagnostics. The possibility of familial hypertriglyceridemia should be considered with a moderate increase in plasma triglyceride levels against the background of normal cholesterol levels. In most patients, the plasma is clear or slightly cloudy in appearance. After standing in the refrigerator overnight, the chylomicrons usually do not form a top layer. With plasma electrophoresis, an increase in pre-R- fractions (lipoproteinemia, type 4). As already mentioned, in some patients, hypertriglyceridemia may be sharply expressed against the background of an increased number of chylomicrons and VLDL. In these cases, when plasma is stored in the refrigerator overnight, an upper creamy layer (chylomicrons) forms in it over the cloudy (VLDL) contents of the test tube (lipoproteinemia, type 5).

In each individual case of an increase in the level of VLDL, regardless of the concomitant increase in the level of chylomicrons, it is rather difficult to decide whether the patient suffers from familial hypertriglyceridemia or his hypertriglyceridemia is due to some other genetic or acquired defect, for example, mixed hyperlipidemia or sporadic hypertriglyceridemia.

In typical cases of familial hypertriglyceridemia, half of the first-degree relatives have hypertriglyceridemia, but not isolated hypercholesterolemia. Determination of plasma lipids in children in this case is useless, since the disease, as a rule, does not manifest itself until puberty.

Treatment. An attempt should be made to reduce the effect of all complicating conditions. With obesity, limit the calorie intake of food. It is also necessary to reduce its saturated fat content. Alcohol and oral contraceptives should be avoided. Diabetes mellitus requires appropriate intensive treatment. It is necessary to determine the function of the thyroid gland and, if hypothyroidism is detected, appropriate treatment. If all these methods are ineffective, nicotinic acid or gemfibrozil can be prescribed, which help some patients. The mechanism of action of these drugs is not clear enough. In patients with severe hypertriglyceridemia, a diet that includes fish oil is often very effective.

T.P. Harrison. Principles of internal medicine.Translation by Ph.D. A. V. Suchkova, Ph.D. N.N. Zavadenko, Ph.D. D. G. Katkovsky

Lipid metabolismit is a complex biochemical process in the cells of an organim, which includes the breakdown, digestion, absorption of lipids in the digestive tract. Lipids (fats) enter the body with food.

Lipid metabolism disorders leads to the emergence of a number of diseases. The most important among them are atherosclerosis and obesity. Diseases of the cardiovascular system are one of the most common causes of death. The predisposition to the occurrence of cardiovascular diseases is a serious reason for examinations. People at risk should closely monitor their health. A number of diseases are caused by violation of lipid metabolism... The most important among them should be called atherosclerosis and obesity... Diseases of the cardiovascular system, as a consequence of atherosclerosis, rank first in the structure of mortality in the world.

Lipid metabolism disorders

Manifestation atherosclerosis in the defeat of the coronary vessels of the heart. The accumulation of cholesterol in the walls of blood vessels leads to the formation of atherosclerotic plaques. They, increasing in size over time, can block the lumen of the vessel and interfere with normal blood flow. If as a result of this, blood flow is disturbed in the coronary arteries, then there is myocardial infarction(or angina pectoris). The predisposition to atherosclerosis depends on the concentration of transport forms of blood lipids, plasma alpha-lipoproteins.

Accumulation cholesterol in the vascular wall occurs due to an imbalance between its entry into the vascular intima and its exit. As a result of this imbalance, cholesterol accumulates there. In the centers of accumulation of cholesterol, structures are formed - atheromas. Known two factors, which cause a violation of lipid metabolism. First, changes in LDL particles (glycosylation, lipid peroxidation, phospholipid hydrolysis, apo B oxidation). Secondly, the ineffective release of cholesterol from the endothelium of the vascular wall by circulating HDL in the blood. Factors affecting elevated LDL levels in humans:

saturated fat in the diet;

high intake of cholesterol;

a diet low in fibrous foods;

alcohol consumption;

pregnancy;

obesity;
alcohol;

hypothyroidism;

cushing's disease;
hereditary hyperlipidemia.

Lipid metabolism disorders are the most important risk factors for the development of atherosclerosis and related diseases of the cardiovascular system. Plasma concentration of total cholesterol or its fractions is closely correlated with morbidity and mortality from coronary heart disease and other complications of atherosclerosis. Therefore, the characteristic of lipid metabolism disorders is a prerequisite for effective prevention. cardiovascular disease.Lipid metabolism disorders can be:

Primary;

secondary.

Lipid metabolism disorders are of three types:

isolated hypercholesterolemia;

isolated hypertriglyceridemia;

mixed hyperlipidemia.

Primary lipid metabolism disorder can be diagnosed in patients with early onset of atherosclerosis (up to 60 years). A secondary disorder of lipid metabolism occurs, as a rule, in the population of developed countries as a result of:

cholesterol nutrition;

passive lifestyle;

sedentary work;

Hereditary factors.

In a small number of people, hereditary disorders of lipoprotein metabolism are observed, manifested in hyper- or hypolipoproteinemia. Their cause is a violation of the synthesis, transport or cleavage of lipoproteins.

In accordance with the generally accepted classification, there are 5 types of hyperlipoproteinemia.

1. The existence of type 1 is due to insufficient LPL activity. As a result, chylomicrons are very slowly removed from the bloodstream. They accumulate in the blood, and the level of VLDL is also above normal.
2. Type 2 hyperlipoproteinemia is divided into two subtypes: 2a, characterized by high levels of LDL in the blood, and 2b (increased LDL and VLDL). Type 2 hyperlipoproteinemia is manifested by high, and in some cases very high, hypercholesterolemia with the development of atherosclerosis and ischemic heart disease. The content of triacylglycerols in the blood is within normal limits (type 2a) or moderately increased (type 2b). Type 2 hyperlipoproteinemia is characteristic of a serious illness - hereditary hypercholesterolemia that affects young people. In the case of the homozygous form, it ends in death at a young age from myocardial infarction, strokes and other complications of atherosclerosis. Type 2 hyperlipoproteinemia is widespread.
3. In type 3 hyperlipoproteinemia (dysbetalipoproteinemia), the conversion of VLDL to LDL is disturbed, and pathological floating LDL or VLDL appears in the blood. The blood levels of cholesterol and triacylglycerols are increased. This type is quite rare.
4. In type 4 hyperlipoproteinemia, the main change is an increase in VLDL. As a result, the content of triacylglycerols in blood serum is significantly increased. It is combined with atherosclerosis of the coronary vessels, obesity, diabetes mellitus. It develops mainly in adults and is very common.
5. 5th type of hyperlipoproteinemia - an increase in the serum content of HM and VLDL, associated with a moderately reduced activity of lipoprotein lipase. The concentration of LDL and HDL is below normal. The content of triacylglycerols in the blood is increased, while the concentration of cholesterol is within the normal range or moderately increased. It occurs in adults, but is not widespread.
Typing of hyperlipoproteinemia is carried out in the laboratory on the basis of the study of the content of various classes of lipoproteins in the blood by photometric methods.

Cholesterol in HDL is more informative as a predictor of atherosclerotic lesions of the coronary vessels. Even more informative is the coefficient reflecting the ratio of atherogenic drugs to antiatherogenic drugs.

The higher this coefficient, the greater the risk of the onset and progression of the disease. In healthy individuals, it does not exceed 3-3.5 (in men it is higher than in women). In patients with coronary artery disease, it reaches 5-6 or more units.

Is diabetes a disease of lipid metabolism?

The manifestations of lipid metabolism disorders are so strongly pronounced in diabetes that diabetes is often called a disease of lipid metabolism rather than carbohydrate metabolism. The main disorders of lipid metabolism in diabetes are increased lipid breakdown, an increase in the formation of ketone bodies, and a decrease in the synthesis of fatty acids and triacylglycerols.

In a healthy person, usually 50% of the incoming glucose is decomposed by CO2 and H2O; about 5% is converted to glycogen, and the rest is converted to lipids in fat stores. In diabetes, only 5% of glucose is converted to lipids, while the amount of glucose that breaks down to CO2 and H2O also decreases, and the amount converted to glycogen changes insignificantly. The result of a violation of glucose consumption is an increase in the level of glucose in the blood and its removal in the urine. Intracellular glucose deficiency leads to a decrease in the synthesis of fatty acids.

In untreated patients, there is an increase in plasma levels of triacylglycerols and chylomicrons and plasma is often lipemic. An increase in the level of these components causes a decrease in lipolysis in fat stores. A decrease in lipoprotein lipase activity further contributes to a decrease in lipolysis.

Lipid peroxidation

A feature of cell membrane lipids is their significant unsaturation. Unsaturated fatty acids are easily subject to peroxide destruction - LPO (lipid peroxidation). The membrane response to damage is therefore called “peroxide stress”.

LPO is based on a free radical mechanism.
Free radical pathology is smoking, cancer, ischemia, hyperoxia, aging, diabetes, i.e. practically in all diseases there is an uncontrolled formation of free oxygen radicals and intensification of lipid peroxidation.
The cage has a system of protection against free radical damage. The antioxidant system of cells and tissues of the body includes 2 links: enzymatic and non-enzymatic.

Enzymatic antioxidants:
- SOD (superoxide dismutase) and ceruloplasmin, involved in the neutralization of free oxygen radicals;
- catalase, which catalyzes the decomposition of hydrogen peroxide; the glutathione system, providing catabolism of lipid peroxides, peroxide modified nucleotides and steroids.
Even a short-term lack of non-enzymatic antioxidants, especially antioxidant vitamins (tocopherol, retinol, ascorbate), leads to permanent and irreversible damage to cell membranes.

Dyslipidemia belongs to metabolic disorders in the human body. This is a pathological condition in which the normal lipid composition of the blood changes. It is not an independent disease. Hyperlipoproteinemia is a major risk factor for atherosclerosis.

Violation of fat metabolism

Lipid disorders are very common. This pathology is diagnosed mainly in adults. Triglycerides, cholesterol and lipoproteins are synthesized in the human body. The latter are formed by proteins and fats. Allocate lipoproteins of high, low, intermediate and very low density. In addition to these compounds, there are chylomicrons.

Lipoproteins are essential for cholesterol transport and cell building. When fat metabolism is disturbed, the ratio of these substances changes and their formation increases. There is such a thing as hyperlipoproteinemia. This is a high level of lipoproteins in the blood. It is a risk factor for the development of cardiovascular pathology (coronary artery disease, atherosclerosis, hypertension).

Tens of millions of people die from this disease every year. Normally, the cholesterol level of a healthy person does not exceed 5.2 mmol / l. A high concentration of this substance is more than 6.2 mmol / l. The optimal blood triglyceride level is less than 1.7 mmol / L. Low density lipoproteins are atherogenic. They increase the likelihood of developing atherosclerosis.

Normally, their concentration in the blood is less than 2.6 mmol / l. A borderline condition is when the LDL content is 3.4–4 mmol / l. High density lipoproteins are antiatherogenic. Their low concentration is a risk factor for the development of cardiovascular pathology. The optimum is the HDL content of 1.6 mmol / l and higher.

Types of lipid metabolism disorders

All types of hyperlipidemia are known to experienced physicians. This pathology is primary, secondary and alimentary. In the first case, the disorders are caused by congenital (genetic) factors. The primary polygenic form of this pathology is most often diagnosed. The secondary type develops against the background of other diseases. Alimentary - due to a balanced diet.

There is a classification of hyperlipoproteinemias depending on the content of which compounds are increased. The following types are distinguished according to Fredrickson:

hereditary hyperchylomicronemia;
hereditary and polygenic;
combined hyperlipidemia;
hereditary dis-beta lipoproteinemia;
endogenous hyperlipidemia;
hereditary hypertriglyceridemia.

There are 5 types of them in total. The second form is subdivided into types 2a and 2b. Disorder of type 2a fat metabolism is characterized by a high concentration of LDL in the blood. With the 2b-form, the content of triglycerides, VLDL and LDL increases. With type 3, a high concentration of LDL is observed. 4 form of this pathology is characterized by an increased content of VLDL in the blood. With type 5, the synthesis of chylomicrons is additionally enhanced.

Causes of occurrence

These changes occur for several reasons. The main etiological factors are:

inheritance of defective genes from parents;
diabetes;
insufficient production of thyroid hormones;
surgery on the thyroid gland;
cholelithiasis;
cholecystitis;
hepatitis;
taking certain medications;
poor nutrition;
chronic renal failure;
passive lifestyle.

The uncontrolled use of immunosuppressants, beta-blockers, thiazide diuretics, hormonal drugs, retinoids and hormonal drugs (estrogens, corticosteroids) adversely affects fat metabolism. Diabetic hyperlipidemia is common. It is observed in people whose dietary calorie content exceeds the norm.

The secondary form of hyperlipidemia is observed against the background of nephrotic syndrome. The risk group includes pregnant women. An alimentary form of dyslipidemia is often diagnosed. It is caused by an excess in the diet of fatty foods (pork, sausages, offal), overeating and abuse of confectionery and bakery products.

The contributing factors are:

stressful situations;
sedentary work;
persistent hypertension;
large waist circumference;
age over 45;
burdened family history;
the presence of a stroke or coronary heart disease.

This pathology is more common in men.

Manifestations of disorders of fat metabolism

With hyperlipidemia, there are no specific symptoms. This is a laboratory indicator, not a disease. When the lipid composition of the blood changes, the following symptoms are possible:

a yellowish or white ring in the corneal area;

If the atherogenic fraction of lipoproteins is increased, then development is possible. It affects the eyelids. Xanthelasmas are yellow, round or oval formations. They rise above the skin. This condition most often develops in people with types 2 and 3 dyslipidemia. The risk group includes older women. Sometimes, with a violation of fat metabolism, corneal opacity is observed.

External symptoms of elevated blood lipids include xanthomas. They can be localized on the buttocks, thighs, fingers, and also in the area of \u200b\u200bthe joints. Xanthomas are formed by triglycerides, cholesterol and phagocytes. In types 2 and 3 of dyslipidemia, yellow spots often appear in the tendon area. localized in the folds of the skin.

With this violation, the development of atherosclerosis is possible. The clinical picture is determined by the localization of the pathological process. Symptoms such as headache, weakness, stool disorder, chest pain, abdominal pain, cramps, swelling and paresthesia of the extremities are possible. When pancreatitis often develops. It manifests itself as abdominal pain, stool disturbance, and bloating.

Survey

Treatment of hyperlipidemia begins after the diagnosis is clarified. For this you will need:

In the presence of subjective complaints, tomography, duplex scanning, ultrasound Doppler and electrocardiography may be required. It is very important to establish the underlying risk factors for dyslipidemia. This laboratory syndrome is detected during the lipid profile.

Before the study, you must:

follow a strict diet for 2-3 weeks;
cure existing infectious diseases;
avoid the application of a tourniquet.

During the study, the doctor determines the content of total cholesterol, lipoproteins and triglycerides.

Therapeutic tactics

In secondary dyslipidemia, treatment is directed at the underlying disease (diabetes, kidney or thyroid disease). The mixed form of this pathology requires an integrated approach to treatment.

The main aspects of therapy are:

normalization of weight;
dosing load;
adherence to a diet;
refusal from alcohol and cigarettes.

Hyperlipidemia of any degree is an indication for a change in diet. Patients need:

According to the indications, the following medications can be prescribed:

cholesterol absorption inhibitors;
preparations based on polyunsaturated fatty acids;

These medications lower blood lipids. Statins are most effective. Appointed, Atoris, Vero and Symbor. Extracorporeal treatments are widely used. These include immunosorption, plasma filtration and hemosorption. The diet must be followed at all times.

Patients need to increase physical activity, ensure adequate nighttime sleep and eliminate stressful situations.

Unspecified hyperlipidemia, if untreated, leads to atherosclerosis and hemodynamic disturbances. Thus, high lipoprotein levels are most often associated with malnutrition and hereditary predisposition.

Type II hyperlipoproteinemia (hypercholesterolemia)accounts for about 30% of cases of hyperlipidemia, is associated with a decrease in catabolism or increased synthesis of beta-lipoproteins.

What provokes Type II Hyperlipoproteinemia:

hyperbetalipoproteinemia

inherited in an autosomal dominant manner.

Pathogenesis (what happens?) During Type II Hyperlipoproteinemia:

Hereditary type IIa hyperlipoproteinemia develops as a result of mutations in the LDL receptor gene (0.2% of the population) or the apoB gene (0.2% of the population).

Symptoms of Type II Hyperlipoproteinemia:

Clinical manifestations in homozygotes occur in childhood, in heterozygotes - at the age of over 30 years. Characterized by xanthomas in the Achilles tendon, extensor tendons of the feet and hands, periorbital xanthelasms. Signs of early atherosclerosis are often noted, and deaths from myocardial infarction in childhood and adolescence have been described.

Sometimes combined with corneal lipid arch and xanthomatosis. It is characterized by a high risk of rapid and early (even in the 2-3rd decade of life) development of atherosclerosis or sudden death.

Diagnosis of Type II Hyperlipoproteinemia:

In the blood, the content of beta-lipoproteins is increased, the amount of cholesterol is sharply increased, the concentration of triglycerides is normal, the coefficient of cholesterol: triglycerides is more than 1.5. Blood plasma after standing in the refrigerator for 12-24 h remains transparent.

Treatment of Type II Hyperlipoproteinemia:

Treatment is reduced to pathogenetic correction of metabolic and clinical syndromes.

For patients with primary and secondary hyperlipoproteinemia and normal body weight, a 4-time meal is recommended, with obesity

5-6 times, since rare meals contribute to an increase in body weight, a decrease in glucose tolerance, the occurrence of hypercholesterolemia and hypertriglyceridemia. The main calorie intake should be in the first half of the day. for example, with 5 meals a day, the 1st breakfast should be 25% of the daily calorie content, the 2nd breakfast, lunch, afternoon tea and dinner

respectively 15, 35, 10 and 15%. General strengthening therapy is also carried out; with obesity, sufficient physical activity is required.

In type I hyperlipoproteinemia, heparin and other hypolipidemic agents have no effect. In pediatric practice, it is preferable to use drugs of milder action: cholestyramine, clofibrate, etc. In some cases, for easier adaptation of the patient to the diet, anorexigenic drugs are prescribed for a short time.

Effective methods of treating alipoproteinemia and hypolipoproteinemia have not been developed.

Michael S. Brown, Joseph L. Goldstein

Hyperlipoproteinemias are lipid transport disorders caused by accelerated synthesis or delayed destruction of lipoproteins that carry cholesterol and triglycerides in plasma. The increase in plasma lipoprotein levels is of clinical importance because they can cause the development of two serious, life-threatening diseases - atherosclerosis and pancreatitis. Reducing the amount of cholesterol contained in lipoproteins, carried out with the help of diet and drugs, reduces the risk of myocardial infarction in hyperlipoproteinemia. Some hyperlipoproteinemias are directly caused by the primary disruption of the synthesis and destruction of lipoprotein particles. Others develop secondary, that is, an increase in the level of lipoproteins in the plasma is one of the manifestations of anomalies associated with a violation of regulatory metabolic systems, for example, with a deficiency of thyroid hormones or insulin. Primary hyperlipoproteinemia can be divided into two large groups: 1) single gene disorders, which are transmitted by a simple dominant or recessive mechanism; 2) multifactorial disorders with a complex pattern of inheritance, in which hyperlipoproteinemias of varying severity in members of the same family are caused by the interaction of weak effects of numerous variant genes with the effects of environmental factors.

The role of lipoproteins in lipid transport

Lipoproteins are globular particles of high molecular weight that carry non-polar lipids (mainly triglycerides and cholesterol esters) in plasma. The general model of the structure of the lipoprotein particle is shown in Fig. 315-1. Each particle contains a non-polar core in which a large number of hydrophobic lipid molecules are packed in the form of an oil droplet. This hydrophobic core, which accounts for most of the mass of the entire particle, consists of triglycerides and cholesterol esters in various ratios. The core is surrounded by a polar surface coat of phospholipids, which stabilizes the lipoprotein particle, ensuring its solubility in plasma. In addition to phospholipids, the polar shell contains small amounts of unesterified cholesterol. Each lipoprotein particle also contains specific proteins (called apoproteins) that are located on its surface. Apoproteins bind to specific enzymes or transport proteins on the cell membrane, thereby directing the lipoprotein to the sites of its metabolism.

Table 315-1 describes the characteristics of the five main classes of lipoproteins that normally circulate in human plasma. These classes differ in the composition of non-polar lipids in the core, the composition of apoproteins, as well as density, size, and electrophoretic mobility.

Lipid transport: an exogenous pathway. In fig. 315-2 depicts the pathways by which lipoproteins transport lipids in plasma. The largest amount of lipoproteins is involved in the transfer of fat from food, which contains more than 100 g of triglycerides and about 1 g of cholesterol per day. In intestinal epithelial cells, dietary triglycerides and cholesterol are incorporated into large lipoprotein particles called chylomicrons. The latter are secreted into the intestinal lymph and through the general bloodstream enter the capillaries of adipose tissue and skeletal muscles, where they interact with the binding sites of the capillary walls. Being associated with these areas of the endothelial surface, chylomicrons are nevertheless subject to the action of the enzyme lipoprotein lipase. Chylomicrons contain a special apoprotein C II, which activates lipase, which releases free fatty acids and monoglycerides (Fig. 315-3). Fatty acids pass through the endothelial cell and enter adjacent adipocytes or muscle cells, in which they are either re-esterified into triglycerides or oxidized.

Figure: 315-1. Schematic representation of the structure of a typical plasma lipoprotein particle (a) and two non-polar lipids (b). The core of the spherical lipoprotein particle (a) consists of two non-polar lipids - triglyceride and cholesterol esters, the amounts of which are different in different lipoproteins. The non-polar core is surrounded by a surface envelope consisting predominantly of phospholipids. Apoproteins are on the surface and reach the core. Different amounts of unesterified cholesterol are included in the phospholipid layer of the surface shell. The qualitative composition of each of the five main classes of lipoprotein particles in human plasma, see table. 315-1. For the assimilation of two non-polar lipids - triglyceride and cholesterol ester (b), tissues need to break the ester bonds between fatty acids and glycerol (triglyceride) or cholesterol (cholesterol ester), which occurs under the action of lipoprotein lipase and lysosomal cholesterol esterase, respectively.

After removal of triglycerides from the core, the remainder of the chylomicron is separated from the capillary epithelium and re-enters the bloodstream. Now it has become a particle containing a relatively small amount of triglycerides and a large amount of cholesterol esters. There is also an exchange of apoproteins between it and other plasma lipoproteins. The final result is the conversion of the chylomicron into a particle of its residue, rich in cholesterol esters, as well as apoproteins B-48 and E. These residues are transferred to the liver, which absorbs them very intensively. This uptake is mediated by the binding of apoprotein E to a specific receptor called the chylomicron residue receptor on the surface of the hepatocyte. Bound residues are taken up by the cell and degraded in the lysosomes in a process called receptor-mediated endocytosis (see Figure 315-3). The overall result of the transport process carried out by chylomicrons is the delivery of food triglycerides to adipose tissue and cholesterol to the liver.

Figure: 315-2. Scheme of transport of triglycerides and cholesterol in human plasma (see the text for details).

VLDL - very low density lipoproteins, IDL - intermediate density lipoproteins, LDL-low-density lipoproteins, HDL-high-density lipoproteins, LCAT-lecithin; cholesterol acyltransferase, LP - lipase, lipoprotein lipase, FFA - free fatty acids. The main apoproteins of each lipoprotein class are presented. Other apoproteins are also present (see Table 315-1).

Some of the cholesterol entering the liver is converted into bile acids, which are released into the intestines, where they act as detergents and facilitate the absorption of dietary fat. In addition, some of the cholesterol goes into bile without being converted to bile acids. The liver supplies cholesterol to other tissues in a so-called endogenous route, which is discussed below.

Lipid transport: an endogenous pathway. The synthesis of triglycerides in the liver is enhanced by the consumption of foods with a large amount of carbohydrates. In the liver, carbohydrates are converted into fatty acids, esterified by glycerol to form triglycerides secreted into the bloodstream in the nucleus of very low density lipoproteins (VLDL). VLDL particles are relatively large, contain 5-10 times more triglycerides than cholesterol esters, and contain one of the forms of apoprotein B, called B-100, which differs from apoprotein B-48, which is characteristic of chylomicrons (Table 315- one).

VLDL particles enter the tissue capillaries, in which they interact with the same enzyme - lipoprotein lipase, which destroys chylomicrons. The triglyceride core of VLDL is hydrolyzed and fatty acids are used to synthesize triglycerides in adipose tissue. Particle residues resulting from the action of lipoprotein lipase on VLDL are called intermediate density lipoproteins (IDLs). Some of the particles of LDL are degraded in the liver by binding to receptors called low density lipoprotein receptors (LDL receptors), which are different from the receptors for chylomicron residues. The rest of the DID remains in the plasma, in which it undergoes further transformation, during which almost all remaining triglycerides are removed. During this transformation, the particle loses all its apoproteins, with the exception of apoprotein B-100. As a result, a cholesterol-rich LDL particle is formed from the LDL particle. The core of LDL is almost entirely composed of cholesterol esters, and the surface shell contains only one apoprotein - B-100. In humans, a fairly large part of LDL is not absorbed by the liver, and therefore their level in human blood is relatively high. Indeed, normally about 3/4 of the total cholesterol in human plasma is contained in LDL particles.

Figure: 315-3. Comparison of the mechanisms by which triglyceride-rich lipoproteins (a) and cholesterol-rich lipoproteins (b) deliver their core lipids to target tissues. Triglycerides are hydrolyzed by the extracellular enzyme lipoprotein lipase (LPL), which is attached to endothelial cells and acts on its surface. Cholesterol esters are hydrolyzed by an intracellular enzyme - acidic lipase, localized in lysosomes and cleaving the esters that enter the cell by receptor-mediated endocytosis. TG - triglycerides, VLDL - very low density lipoproteins, EC - cholesterol esters, IDL - intermediate density lipoproteins, LDL - low density lipoproteins, FFA - free. fatty acid. Apoproteins responsible for interaction with the enzyme and receptors (SP, B and E) are presented.

One of the functions of LDL is to supply cholesterol to a variety of extrahepatic parenchymal cells such as adrenal cortex cells, lymphocytes, muscle cells, and kidney cells. All of them carry LDL receptors on their surface. LDL bound to these receptors are absorbed through receptor-mediated endocytosis and are destroyed inside cells by lysosomes (see Fig. 315-3). Esters of LDL cholesterol are hydrolyzed by lysosomal cholesteryl esterase (acidic lipase), and free cholesterol is used for membrane synthesis and as a precursor for steroid hormones. Like extrahepatic tissue, the liver possesses multiple LDL receptors; in it, LDL cholesterol is used to synthesize bile acids and to form free cholesterol secreted into bile. In humans, 70-80% of LDL is removed from plasma daily by receptor-mediated pathway. The rest is destroyed by the cellular system of "cleaners" - phagocytic cells of the reticuloendothelial system. In contrast to the receptor-mediated pathway for the destruction of LDL, the pathway of their destruction in "cleanser" cells is believed to serve exclusively for the destruction of LDL when their level in plasma increases, and not for supplying cells with cholesterol.

Table 315-1. Characteristics of the main classes of lipoproteins in human plasma

As the membranes of the parenchymal cells and the "cleaners" cells undergo a cycle and as cells die and renew, unesterified cholesterol enters the plasma, in which it is usually bound by high density lipoprotein (HDL). This unesterified cholesterol then forms esters with fatty acids by the enzyme lecithin cholesterol acyltransferase (LCAT) present in plasma. The cholesterol esters formed on the surface of HDL are transferred to VLDL and ultimately incorporated into LDL. Thus, a cycle is formed in which LDL delivers cholesterol to extrahepatic cells and re-receives it from them through HDL. Most of the cholesterol released by extrahepatic tissues is carried to the liver, where it is excreted in bile.

Diagnostics of the hyperlipoproteinemia. Plasma levels of one class of lipoproteins or several are increased in many diseases. As a rule, they are detected by an increase in the concentration of triglycerides or cholesterol in plasma on an empty stomach, that is, by a condition called hyperlipidemia. Plasma cholesterol levels reflect total cholesterol, which includes both ester cholesterol and unesterified cholesterol. By the content of cholesterol and triglycerides in plasma, one can judge the nature of lipoprotein particles, the level of which is increased in this case. An isolated increase in plasma triglyceride levels indicates an increase in the concentration of chylomicrons or VLDL. On the other hand, an isolated increase in cholesterol levels almost always indicates an increase in LDL concentration. Often, both triglyceride and cholesterol levels rise simultaneously. This may reflect a sharp increase in the concentration of chylomicrons and VLDL, but in this case, the ratio of triglycerides to cholesterol in plasma should exceed 5: 1. An alternative is to simultaneously increase the content of VLDL and LDL, but the ratio of triglycerides / cholesterol in plasma is usually less than 5: 1.

The definition of hyperlipoproteinemia is rather arbitrary, since the levels of lipids and lipoproteins in plasma in different individuals are distributed along a bell-shaped curve without a clear distinction between norm and pathology. Since diet and other environmental factors affect lipoprotein concentration, standards need to be set for specific populations. Usually, the statistical limits of fluctuations in the norm are chosen arbitrarily, based on the results of examining a large number of practically healthy individuals of different ages. The border is most often drawn within the upper concentrations, which are recorded in 5-10% of healthy people (i.e., at the level of the 90-95th percentile). However, the results of a blood test for lipids in residents of industrial and predominantly agricultural regions indicate that statistically "normal" lipid and lipoprotein concentrations do not necessarily mean the absence of pathology. As a working rule, hyperlipoproteinemia is considered significant in any person under the age of 20, whose total cholesterol or triglyceride levels in plasma exceed 1900 mg / L and 1400 mg / L, respectively. In persons over the age of 20, this condition is diagnosed when the plasma level of total cholesterol and triglycerides is above 2200 mg / l and 2000 mg / l, respectively.

Various combinations of lipoproteins, the level of which is increased in pathology, are divided into six types or categories (table. 315-2). Most of them can be caused by various genetic diseases (Table 315-3). Conversely, in some genetic diseases, hyperlipoproteinemia of not one but several types can be diagnosed. In addition, any type of hyperlipoproteinemia may be secondary to another metabolic disorder (Table 315-4). Consequently, the types of lipoproteinemia should be considered as evidence of a violation of lipoprotein metabolism, and not as a name for a specific disease.

Table 315-2. The nature of the increase in plasma lipoproteins (types of lipoproteinemia)

To recognize the type of lipoproteinemia present, a simple determination of plasma lipid levels in conjunction with clinical findings is usually sufficient (see Table 315-2). Sometimes, in cases of suspicion of an increase in the level of lipoprotein residues (type 3 lipoproteinemia, in which a "broad beta" band is electrophoretically detected) or for chylomicronemia (type 1 lipoproteinemia), plasma paper electrophoresis is used. In rare cases, the content of HDL is determined, since a high level of lipoproteins of this class is statistically associated with a decrease in the risk of myocardial infarction (see Chapter 195). HDL concentration can be determined in clinical laboratories using standardized lipoprotein separation techniques, but the value of such determinations in predicting the occurrence of myocardial infarction in an individual patient remains problematic.

Primary hyperlipoproteinemias due to single gene mutation

Familial lipoprotein lipase deficiency. This rare autosomal recessive disorder is thought to be the result of the absence or abrupt decrease in lipoprotein lipase activity. As a result of this disorder, the metabolism of chylomicrons is blocked, which leads to their extreme accumulation in plasma.

Clinical manifestations. Pathology usually manifests itself in infancy or childhood with recurrent attacks of abdominal pain. They are caused by pancreatitis associated with a sharp increase in plasma chylomicrons.

Table 315-3. Characterization of primary hyperlipoproteinemias due to single gene mutation

Table 315-4. Clinical conditions accompanied by secondary hyperlipoproteinemia

Patients periodically develop eruptive xanthomas: small yellow papules, often surrounded by an erythematous ring, mainly on the skin of the gluteal region and other areas of the body experiencing pressure. Xanthomas are formed as a result of the deposition of large amounts of chylomicron triglycerides in the skin histiocytes. Triglycerides are also deposited in phagocytes of the reticuloendothelial system, causing hepatomegaly, splenomegaly and infiltration of bone marrow by foam cells. With a sharp increase in the level of chylomicrons in the blood (i.e., when the level of triglycerides in plasma is above 20 g / l), it acquires a milky yellow color, and it is called lipemic. When examined with an ophthalmoscope, a whitish retina and white vessels in it are visible, allowing the diagnosis of retinal lipemia. Despite the sharp increase in plasma triglycerides, the development of atherosclerosis is not accelerated.

Pathogenesis. Patients are homozygotes for a mutation that prevents the normal expression of lipoprotein lipase activity. The primary genetic defect seems to affect the very structure of the enzyme: the amount of lipoprotein lipase activator - apoprotein C-II - is not changed. The patient's parents are obligate heterozygotes for a lipoprotein lipase defect, but from a clinical point of view they are healthy. As a result of lipoprotein lipase deficiency in homozygotes, chylomicrons cannot be metabolized normally, therefore, after ingestion of fatty foods, their level increases markedly. If in a healthy person chylomicrons disappear from the blood 12 hours after a meal, then in a patient their high level persists even after several days against the background of fasting or consumption of low-fat food.

Chylomicrons in the blood, passing through the capillaries of the pancreas, cause inflammation. In the lumen of the capillaries, small amounts of lipase leaking from the tissue of the gland act on them. As a result of partial hydrolysis of triglycerides and phospholipids of chylomicrons, toxic products are formed, including fatty acids and lysolecithin, destroying tissue membranes, and therefore, the release of lipase from acinar cells is enhanced, which ultimately leads to an acute attack of pancreatitis.

Diagnostics. The diagnosis of familial lipoprotein lipase deficiency should be assumed when lipemic plasma is detected in young people who have been fasting for at least 12 hours. Plasma collected in the presence of EDTA after overnight standing in a refrigerator at 4 ° C in this case takes on a characteristic appearance: a white creamy layer (consisting of chylomicrons) appears on top, under which there is a transparent plasma. The diagnosis of familial lipoprotein lipase deficiency is confirmed by electrophoresis, which allows the detection of type I lipoproteinemia. The diagnosis is confirmed by the absence of an increase in plasma lipoprotein lipase activity after heparin administration. In a healthy person, intravenous administration of heparin is accompanied by the release of lipoprotein lipase from its binding sites in the capillary endothelium; therefore, the level of the enzyme rises in the plasma. Using gel electrophoresis of VLDL apoproteins in patients with lipoprotein lipase deficiency, a normal amount of its activator, apoprotein C-II, is found, which makes it possible to differentiate them from patients with a similar disorder - familial insufficiency of apoprotein C-II (see below).

Treatment. Symptoms become less pronounced if the patient is transferred to a low-fat diet. Every effort should be made to maintain fasting plasma triglyceride levels below 10 g / L to prevent the development of pancreatitis. It has been empirically established that in order to prevent symptomatic hyperlipemia, a sick adult must constantly consume fat in an amount of less than 20 g / day. Since medium chain triglycerides are not incorporated into chylomicrons, these are the fats that should be used in the diet to ensure adequate calories. The patient must also receive fat-soluble vitamins.

Familial insufficiency of apoprotein C-II. This rare autosomal recessive disorder is caused by the absence of apoprotein C-II, an essential cofactor for lipoprotein lipase. A deficiency of this peptide leads to a functional deficiency of the enzyme and thus to the emergence of a syndrome similar to familial lipoprotein lipase deficiency (see earlier), although not identical to it. Due to the deficiency of apoprotein C-II, lipoprotein lipase is not activated and its two lipoprotein substrates accumulate in the blood: chylomicrons and VLDL, which leads to hypertriglyceridemia (lipoproteinemia, type 1 or 5). This disease is diagnosed in children or adults with recurrent attacks of pancreatitis or accidentally detected "milk" plasma. The diagnosis is confirmed by the absence of apoprotein C-II during gel electrophoresis of VLDL apoproteins. Transfusion of healthy human plasma, containing an excess of apoprotein C-II, to patients leads to a sharp decrease in triglyceride levels. In heterozygotes, in which the level of apoprotein C-II is reduced by 50%, the concentration of triglycerides in the plasma may be slightly increased, but pancreatitis does not develop. Treatment consists of adhering to a restricted fat diet throughout the patient's life. In severe pancreatitis, transfusion of one or two portions of normal plasma is indicated. Homozygotes for apoprotein C-II deficiency are usually detected at a later age, their plasma contains large amounts of VLDL, and cutaneous eruptive xanthomas appear less frequently than in patients with familial lipoprotein lipase deficiency. The reasons for these clinical differences have not been established.

Familial hyperlipoproteinemia, type 3. In this congenital disorder, plasma levels of both cholesterol and triglycerides are elevated. This is due to the accumulation of residues in the plasma resulting from the partial destruction of VLDL. Familial type 3 hyperlipoproteinemia, also called familial dysbetalipoproteinemia, is transmitted as a single gene defect but appears to require environmental and / or other genetic factors (discussed below) to manifest.

Clinical manifestations. Patients are characterized by the absence of hyperlipidemia or any clinical symptoms until the age of 20 years. The peculiarity of the clinical picture is given by two types of cutaneous xanthomas: striped palmar xanthomatosis, which is manifested by an orange or yellow color of the folds on the palmar surfaces and fingers, and tuberous, or tuberoeruptive, xanthomas, which are convex skin formations ranging in size from a pea to a lemon. Lumpy xanthomas are usually localized over the elbow and knee joints. There are also xanthelasmas of the eyelids, but they are nonspecific for this disease (see below "Familial hypercholesterolemia").

Familial hyperlipoproteinemia of type 3 is characterized by the rapid development of severe atherosclerosis of the coronary and internal carotid arteries, the abdominal aorta and its branches. The result is early myocardial infarction, strokes, intermittent claudication, and leg gangrene. In patients with clinical manifestations of the disease, the latter are often exacerbated by hypothyroidism, obesity, or diabetes mellitus.

Pathogenesis. Hyperlipidemia is caused by the accumulation of large lipoprotein particles containing both triglycerides and cholesterol esters. These particles are the remnants of chylomicrons formed during their catabolism, and LDLs formed during the destruction of VLDL by lipoprotein lipase. In a healthy person, particles of chylomicron residues are rapidly absorbed by the liver and therefore very rarely found in plasma. Some of the DID is also captured by the liver, and the rest is converted to LDL. In patients with type 3 hyperlipoproteinemia, the uptake of DID and chylomicron residues by the liver is blocked; these lipoproteins accumulate in large quantities in plasma and tissues, causing xanthomatosis and atherosclerosis.

The disease-defining mutation affects the gene that encodes the structure of apoprotein E, a protein normally found in LPD and chylomicron residues. It binds with a very high affinity both the receptor of the residues of chylomicrons and the receptor of the DID. Thus, apoprotein E mediates the rapid uptake of both of these particles by the liver. The gene for apoprotein E in the population is polymorphic. There are three common alleles (E2, E3, and E4) with a frequency of approximately 0.12 in the population; 0.75 and 0.13. Each allele determines the synthesis of a specific form of apoprotein E, which can be detected using isoelectric focusing. Three alleles create six genotypes: E2 / E2, E3 / E3, E4 / E4, E2 / E3, E2 / E4, and E3 / E4. Type 3 hyperlipoproteinemia occurs only in individuals homozygous for the E2 allele (E2 / E2 genotype). The protein encoded by the E2 allele has an impaired ability to bind to hepatic receptors that mediate the uptake of chylomicron and LDD residues. As a result, these particles accumulate in the plasma.

The frequency of the E2 / E2 genotype in the population is approximately 1: 100. However, type 3 hyperlipoproteinemia occurs with a frequency of only 1: 10,000. Thus, only 1% of individuals with the E2 / E2 genotype show symptoms of the disease. Apparently, most homozygotes for the E2 allele have some ability to compensate for the defect in apoprotein E, since other apoproteins, for example, B48 and B100, also mediate binding to hepatic receptors, although less efficiently than apoprotein E. Familial type 3 hyperlipoproteinemia occurs only in those individuals who are not only homozygous for the E2 allele, but are also unable to compensate for the impaired function of the E-protein. The inability to compensate can be determined by the independent inheritance of another defect in lipoprotein metabolism, such as familial hypercholesterolemia or multiple hyperlipoproteinemia (see below). If a person is heterozygous for one of these dominant diseases and at the same time homozygous for the E2 allele, he will develop type 3 hyperlipoproteinemia syndrome. Expression of hyperlipoproteinemia in a person with the E2 / E2 genotype will also cause hypothyroidism, diabetes mellitus or obesity. It should be emphasized that heterozygotes for the E2 allele never develop the clinical syndrome of type 3 familial hyperlipoproteinemia.

Diagnostics. The diagnosis is suggested when palmar or tuberous xanthomas are found in patients with elevated plasma levels of both cholesterol and triglycerides. Xanthomas occur in about 80% of symptomatic patients. It should be thought about in the case of a moderate increase in plasma levels of cholesterol and triglycerides, and when their absolute amounts are almost the same (for example, the levels of both cholesterol and triglycerides are about 3000 mg / l). This, however, is not always the case, especially during an exacerbation of the disease, when the content of triglycerides in plasma may increase to a greater extent than cholesterol.

The diagnosis is confirmed by the results of lipoprotein electrophoresis (lipoproteinemia type 3), when the so-called wide beta band appears. It is due to the presence of residues of chylomicrons and LDPP. The final diagnosis is made in specialized laboratories using two methods. First, it is possible to carry out ultracentrifugation of the plasma with the study of the chemical composition of the VLDL fraction. In patients, it contains DID and residues of chylomicrons with a relatively high ratio of cholesterol to triglycerides. Secondly, the correctness of the diagnosis can be verified by detecting homozygosity for the E2 allele during isoelectric focusing of proteins extracted from residue particles.

Treatment. It is necessary to carefully examine the patient for the detection of latent hypothyroidism, including the determination of the level of thyroid-stimulating hormone (TSH) in plasma. If hypothyroidism is detected, levothyroxine is prescribed. This treatment is accompanied by a sharp decrease in lipid levels in a patient with hypothyroidism. In addition, you should try in every possible way to reduce obesity and compensate for diabetes mellitus with diet and insulin. If these measures are unsuccessful, the patient with type 3 hyperlipoproteinemia is prescribed clofibrate, which causes a sharp and persistent decrease in plasma lipid levels.

Familial hypercholesterolemia. This common autosomal dominant disorder affects about 1 in every 500 people. It is caused by a mutation in the LDL receptor gene. In heterozygotes, a two- and three-fold increase in the level of total cholesterol in plasma is found, which is considered to be the result of an increase in the amount of LDL. In patients with two mutant genes of the LDL receptor (familial homozygous hypercholesterolemia), the plasma LDL cholesterol content increases 6-8 times.

Clinical manifestations. Heterozygotes with familial hypercholesterolemia can be detected already at birth, since the content of LDL cholesterol in their umbilical cord blood and, therefore, total cholesterol is increased 2-3 times. An elevated plasma LDL level persists throughout the patient's life, but symptoms usually appear only after the age of 20-30 years. The most important feature is the premature and accelerated development of coronary atherosclerosis. Myocardial infarction occurs at the age of 20-30 years, and the peak of its frequency is recorded after the age of 30-40 years. Among patients aged 60 years, approximately 85% have had myocardial infarction. In women, its frequency also increases, but the average age at the onset of its appearance in them is 10 years older than in men. Heterozygotes for this defect make up approximately 5% of all patients with myocardial infarction.

The second notable clinical manifestation of heterozygosity for this defect is tendon xanthomas. They are nodular swellings, usually along the Achilles and other tendons near the knee and elbow joints and along the back of the hand. Xanthomas are formed as a result of deposits of esters of LDL cholesterol in tissue macrophages. The macrophages overflow with lipid droplets and turn into foam cells. Cholesterol is also deposited in the soft tissues of the eyelids, forming xanthelasma, and in the cornea, forming a corneal arch. If tendon xanthomas are of diagnostic value in familial hypercholesterolemia, then xanthelasmas and corneal arches are found in many healthy adults. The frequency of tendon xanthomas in familial hypercholesterolemia increases with age, and they occur in about 75% of heterozygotes for this defect. The absence of tendon xanthomas, naturally, does not exclude familial hypercholesterolemia.

About one in a million people in the population inherits both copies of the familial hypercholesterolemia gene and is homozygous for this defect. Plasma LDL cholesterol levels are significantly elevated from birth. Already in newborns, a peculiar type of palmar skin xanthomas is often determined, and by the age of 6 years. They are raised, yellow, flat formations in injured areas of the skin, such as knees, elbows, and buttocks. They almost always develop in the interdigital spaces of the hand, especially between fingers I and II. Tendon xanthomas, corneal arches and xanthelasmas are also characteristic. Atherosclerosis of the coronary arteries is often clinically manifested even before the age of 10 years, and myocardial infarction even at the age of 18 months. In addition, cholesterol deposits in the aortic valve can cause symptoms of aortic stenosis. Usually, homozygotes die of myocardial infarction before the age of 20.

In familial hypercholesterolemia, the frequency of obesity and diabetes mellitus does not increase; in patients, body weight, as a rule, is even less than normal.

Pathogenesis. The primary defect is localized in the LDL receptor gene. Experiments on cultured cells made it possible to identify at least 12 mutant alleles in this locus, which can be combined into three classes. With the most common of them, called receptor-negative, the gene product is devoid of functional activity. With the second most common receptor-defective, the receptor has only 1-10% of normal binding capacity in relation to LDL. In the third, characterized by impaired internalization, a receptor is formed that binds LDL, but does not transfer the bound lipoprotein into the cell. This rare allele causes the so-called internalization defect. Homozygotes possess two mutant alleles at the LDL receptor locus, and therefore their cells are completely or almost completely unable to bind or absorb LDL. In heterozygotes, the LDL receptor locus contains one normal and one mutant allele, so their cells can bind and absorb LDL with an intensity of about half that of normal.

Acceleration of the atherosclerotic process in the coronary arteries in familial hypercholesterolemia is also due to high levels of LDL, which excessively infiltrate the vascular walls when the endothelium is damaged. Large amounts of LDL, which have penetrated into the interstitium of the arterial wall, are inaccessible to the "cleaner" cells, and, in the end, atherosclerosis develops. High levels of LDL can also accelerate platelet aggregation in areas of endothelial damage, thereby contributing to an increase in the size of atherosclerotic plaques (see Chapter 195).

Diagnostics. Heterozygous familial hypercholesterolemia is suggested when an isolated increase in plasma cholesterol levels is detected against the background of unchanged triglyceride concentrations. An isolated increase in cholesterol levels is usually due to an increase in the concentration of only LDL (type 2a). However, most individuals with type 2a hyperlipoproteinemia do not have familial hypercholesterolemia. They have a special form of polygenic hypercholesterolemia, which occupies the upper plateau on the bell-shaped curve of the distribution of cholesterolemia values \u200b\u200bin the general population (see below "Polygenic hypercholesterolemia"). Type 2a hyperlipoproteinemia also accompanies multiple type hyperlipidemia (see below). In addition, it can be a symptom of a variety of metabolic disorders, including hypothyroidism and nephrotic syndrome (see Table 315-4).

Heterozygotes for familial hypercholesterolemia can be distinguished from individuals with polygenic hypercholesterolemia and multiple lipidemia in several ways. First, in familial hypercholesterolemia, plasma cholesterol levels are usually higher. Its concentration of 3500-4000 mg / l is more likely to indicate heterozygous familial hypercholesterolemia than other abnormalities. However, in many patients with heterozygous familial hypercholesterolemia, the cholesterol level is only 2850-3500 mg / l, which does not allow to exclude another pathology. Secondly, tendon xanthomas make it possible to actually cast aside doubts about the diagnosis of familial hypercholesterolemia, since they are usually absent in patients with other forms of hyperlipidemia. Third, if in doubt about the diagnosis, other family members should be examined. With familial hypercholesterolemia, half of the relatives of the first degree of relationship have an elevated plasma cholesterol level. Hypercholesterolemia in relatives is especially informative if it is found in children, since an increase in cholesterol levels in childhood is pathognomonic for familial hypercholesterolemia.

In approximately 10% of heterozygotes for familial hypercholesterolemia, plasma triglyceride levels are simultaneously increased (type 26). In these cases, the disease is difficult to differentiate from multiple type hyperlipidemia. Tendon xanthomas or the detection of hypercholesterolemia in children from the patient's family provide significant assistance in differential diagnosis.

In specialized laboratories, the diagnosis of both heterozygous and homozygous familial hypercholesterolemia can be made by directly determining the number of LDL receptors on cultured skin fibroblasts or freshly isolated blood lymphocytes. Homozygous familial hypercholesterolemia is diagnosed in utero by the absence of LDL receptors on cultured amniotic fluid cells. Mutant genes of the LDL receptor can be identified directly in the patient's genomic DNA using restriction and so-called southern blots (see Chapter 58).

Familial hypertriglyceridemia. This common autosomal dominant abnormality is accompanied by an increase in plasma VLDL levels, leading to hypertriglyceridemia.

Mild to moderate hypertriglyceridemia can be sharply increased by a variety of provoking factors. These include uncompensated diabetes mellitus, alcohol abuse, taking birth control pills containing estrogens, and hypothyroidism. In each case, the plasma triglyceride level may exceed 10 g / L. During periods of exacerbation, patients develop mixed hyperlipidemia, i.e. the concentration of both VLDL and chylomicrons (lipoproteinemia, type 5) increases. A high level of chylomicrons predisposes to the formation of eruptive xanthomas and the development of pancreatitis. After elimination of the effect of passing factors, chylomicron-like particles from the plasma disappear and the concentration of triglycerides returns to the initial level.

Pathogenesis. Familial hypertriglyceridemia is inherited as an autosomal dominant trait, which means a single gene mutation. However, the nature of the mutant gene and the mechanism by which it causes hypertriglyceridemia have not been elucidated. Probably, this disease is genetically heterogeneous, i.e. the phenotype of hypertriglyceridemia in different families can be caused by different mutations.

The increase in the incidence of diabetes and obesity in this syndrome is considered to be accidental and related to the fact that both conditions are usually accompanied by an increase in VLDL production and, therefore, increase hypertriglyceridemia. Family examinations reveal relatives of the patient suffering from diabetes without hypertriglyceridemia and triglyceridemia without diabetes, which indicates the independent inheritance of these diseases. With the simultaneous inheritance of genes for diabetes and hypercholesterolemia, the latter becomes more pronounced, and patients are more likely to attract the attention of doctors. Similarly, in patients with familial triglyceridemia and normal body weight, the level of triglycerides in plasma is increased to a lesser extent than when this disease is combined with obesity, so they are less likely to attract the attention of a doctor. With obesity, hypertriglyceridemia increases and the likelihood of its detection increases.

Diagnostics. The possibility of familial hypertriglyceridemia should be considered with a moderate increase in plasma triglyceride levels against the background of normal cholesterol levels. In most patients, plasma appears to be clear or slightly cloudy. After standing in the refrigerator overnight, the chylomicrons usually do not form a top layer. Plasma electrophoresis shows an increase in the pre -? - fraction (lipoproteinemia, type 4). As already mentioned, in some patients, hypertriglyceridemia may be sharply expressed against the background of an increased number of chylomicrons and VLDL. In these cases, when plasma is stored in the refrigerator overnight, an upper creamy layer (chylomicrons) forms in it over the cloudy (VLDL) contents of the test tube (lipoproteinemia, type 5).

Treatment. An attempt should be made to reduce the effect of all complicating conditions. With obesity, limit the calorie intake of food. It is also necessary to reduce its saturated fat content. Alcohol and oral contraceptives should be avoided. Diabetes mellitus requires appropriate intensive treatment. It is necessary to determine the function of the thyroid gland and if hypothyroidism is detected, appropriate treatment should be carried out. If all these methods are ineffective, nicotinic acid or gemfibrozil can be prescribed, which help some patients. The mechanism of action of these drugs is not clear enough. In patients with severe hypertriglyceridemia, a diet that includes fish oil is often very effective.

Multiple type hyperlipidemia. This common condition, also called familial combined hyperlipidemia, is inherited as an autosomal dominant trait. Patients from the same family usually have one of three different types of lipoproteinemia: hypercholesterolemia (type 2a), hypertriglyceridemia (type 4), or both at the same time (type 2b).

Clinical manifestations. In childhood, hyperlipidemia is absent. An increase in plasma cholesterol and / or triglyceride levels is detected at puberty and persists throughout the patient's life. Usually, the degree of increase in lipid levels is small and variable, so that in patients with one examination, only a slight increase in the amount of cholesterol can be detected, and with another - against this background, only an increase in the level of triglycerides. Xanthomas are not formed. However, premature atherosclerosis develops, and the frequency of myocardial infarction in middle age increases regardless of the patient's gender.

A family history of early coronary artery disease is often present. Mixed hyperlipidemia is found in about 10% of all patients with myocardial infarction. The incidence of obesity, hyperuricemia, and impaired glucose tolerance is increased, especially in patients with hypertriglyceridemia. However, this relationship is not as pronounced as in familial hypertriglyceridemia.

Pathogenesis. The disease is inherited as an autosomal dominant trait, which means a single gene mutation. In family examinations, hyperlipidemia is found in about half of the relatives of the patient of the first degree of relationship. However, the level of lipids in the blood in different patients from the same family varies in the same way as in the same patient at different times. Approximately 1/3 of relatives suffering from hyperlipidemia have hypercholesterolemia (lipoproteinemia, type 2a), 1/3-hypertriglyceridemia (type 4) and 1/3-hypercholesterolemia and hypertriglyceridemia at the same time (type 2b). In the majority of sick relatives, the plasma lipid level is slightly above the 95th percentile of the level in the general population and is periodically within the normal range.

Despite the fact that the degree of genetic heterogeneity (if any) and the nature of the primary biochemical disorder remain unknown, patients have an increased rate of VLDL secretion by the liver. Depending on the interaction of factors that regulate the efficiency of the conversion of VLDL to LDL and LDL catabolism, overproduction of VLDL can be manifested by an increase in the level of either VLDL (hypertriglyceridemia) or LDL (hypercholesterolemia), or both. Diabetes, alcoholism, and hypothyroidism increase the severity of hyperlipidemia.

Diagnostics. There are no clinical or laboratory methods that would make it possible to confidently diagnose multiple type of hyperlipidemia in a patient with hyperlipidemia. Any of the lipoproteinemias (types 2a, 26, and 4) can accompany other conditions (see tables 315-3 and 315-4). However, multiple hyperlipidemia should be suspected in every patient with mild hyperlipoproteinemia that changes over time. The diagnosis is confirmed by detecting different lipoproteinemias in the patient's relatives. Tendon xanthomas in a patient or his relatives or hypercholesterolemia in his relatives under the age of 10 can exclude this diagnosis.

Treatment. Treatment should be aimed at reducing the level of lipids, which are predominantly elevated at the time of examination. Common measures are indicated, such as reducing body weight, limiting saturated fat and cholesterol in the diet, and avoiding alcohol and oral contraceptives. Elevated triglyceride levels can be reduced by the action of niacin or gemfibrozil. With an isolated increase in cholesterol levels, bile acid-binding resins should be prescribed. However, in some patients, a decrease in cholesterol levels due to these activities is accompanied by an increase in triglyceride levels.

Primary hyperlipoproteinemia of unknown etiology

Polygenic hypercholesterolemia. By definition, 5% of people in the population have LDL cholesterol levels above the 95th percentile, so they are diagnosed with hypercholesterolemia (lipoproteinemia type 2a or 2b). On average, out of every 20, one suffers from a heterozygous form of familial hypercholesterolemia and two from multiple type hyperlipidemia. In the remaining 17, hypercholesterolemia is polygenic, caused not by a single mutant gene, but by a complex interaction of numerous genetic and environmental factors.

Most of the factors remain unknown. There are probably subtle genetic differences in many of the processes that regulate cholesterol metabolism. For example, healthy people may have genetic polymorphism of proteins that regulate the rate of absorption of cholesterol in the intestine, the synthesis of bile acids and cholesterol, and the synthesis or destruction of LDL. Any unfavorable combination of these slightly modified proteins with environmental factors, such as a diet high in cholesterol or saturated fat, could cause an increase in plasma cholesterol.

Clinically, polygenic hypercholesterolemia is distinguished from familial and from multiple type hyperlipidemia by: 1) examination of the patient's family members (with polygenic hypercholesterolemia, hyperlipidemia is found in no more than 10% of first-degree relatives, and in two other diseases - in 50% of them) and 2 ) detection of tendon xanthomas (absent in polygenic hypercholesterolemia and multiple type hyperlipidemia, but are determined in about 75% of adult heterozygotes with familial hypercholesterolemia).

In some patients with polygenic hypercholesterolemia, cholesterol can be reduced by limiting the amount of saturated fat and cholesterol in the diet. In other cases, medication is required. In patients of the latter group, probucol is sometimes effective. Cholestyramine with or without nicotinic acid can also be given.

Sporadic hypertriglyceridemia. In addition to some forms of primary hypertriglyceridemia, sometimes endogenous hypertriglyceridemia with or without hyperchylomicronemia is determined in persons whose relatives have not been diagnosed with hyperlipidemia. This condition has been called sporadic hypertriglyceridemia. Patients are a heterogeneous group. Some of them could certainly be attributed to one of the mentioned groups of genetic disorders, if it was possible to determine the level of lipids in a sufficiently large number of relatives. Except for the absence of relatives with hyperlipidemia, individuals with sporadic hypertriglyceridemia cannot be distinguished by clinical signs from patients with those forms of primary hypertriglyceridemia that are caused by mutations of single genes. Because patients with sporadic hypertriglyceridemia may have hyperchylomicronemia and pancreatitis, they should be treated with diet and medication in the same way as for familial disease.

Familial hyperalphalipoproteinemia. This condition is characterized by elevated plasma levels of HDL, also called alpha lipoproteins. Plasma levels of LDL, VLDL and triglycerides remain within normal limits. The increase in HDL levels is accompanied by a slight increase in total plasma cholesterol. Despite an isolated increase in plasma HDL cholesterol levels in some individuals exposed to chlorinated hydrocarbon pesticides, alcoholics, or estrogen-treated patients, in most cases, hyperalphalipoproteinemia has a genetic basis. In some families, it is inherited as an autosomal dominant trait, while in others, a multifactorial or polygenic basis of the disease can be assumed. In some individuals with familial hyperalphalipoproteinemia, distinct clinical manifestations are absent.

"Hyperalphalipoproteinemia is associated with a slight increase in life expectancy and a clear decrease in the incidence of myocardial infarction. The mechanism of the increase in plasma HDL levels in this disease has not been deciphered.

Secondary hyperlipoproteinemia

Secondary hyperlipoproteinemias accompany a variety of clinical conditions (see Table 315-4). The most common forms of secondary hyperlipoproteinemia accompany diabetes mellitus; it develops with alcohol abuse and taking oral contraceptives.

Diabetes. In patients with diabetes mellitus, three types of hypertriglyceridemia are identified. Classic diabetic hyperlipemia is a sharp rise in plasma triglyceride levels with insulin deficiency or insulin resistance over many weeks or months. With a deficiency of insulin in the plasma, the concentration of VLDL progressively increases, and subsequently chylomicrons. Triglyceride levels can be as high as 250 g / L. In this case, eruptive xanthomas, retinal lipemia and hepatomegaly appear. Ketosis is common, but severe acidosis is uncommon. This form of hyperlipemia accompanies only partial insulin deficiency. It can usually be controlled with a low-fat diet and insulin, although triglyceride levels are not always completely normalized.

The second type of hypertriglyceridemia in diabetes is associated with acute ketoacidosis. The patient usually develops a mild degree of hyperlipidemia against the background of an increase in the level of VLDL, but not chylomicrons. Sometimes, however, a noticeable increase in triglyceride levels with the development of retinal lipemia is determined. In these cases, both VLDL and chylomicrons are present in the serum.

With the third type of hypertriglyceridemia, the level of VLDL in plasma increases slightly or moderately, which is not corrected even by adequate compensation of diabetes. This usually occurs in obese patients. Since most patients with compensated diabetes have normal plasma triglyceride levels, some patients with persistent hypertriglyceridemia are likely to have some form of familial hyperlipoproteinemia. Indeed, when examining the family members of the patient, it is revealed that many of them are carriers of a congenital defect characteristic of familial hypertriglyceridemia, which is inherited independently of diabetes mellitus.

Insulin deficiency or insulin resistance in diabetes causes an increase in VLDL levels by two mechanisms. In acute insulin deficiency, VLDL secretion by the liver is enhanced as a secondary response to increased mobilization of free fatty acids from adipose tissue. As the duration of hypoinsulinemia increases, the rate of removal of VLDL and chylomicrons from the blood also decreases due to a decrease in lipoprotein lipase activity.

Alcohol abuse. In many individuals, daily consumption of large amounts of ethanol can cause an asymptomatic increase in plasma triglyceride levels due to an increase in VLDL concentration. However, sometimes ethanol consumption is accompanied by a sharp and clinically manifested hyperlipidemia with an increase in plasma levels of both VLDL and chylomicrons (type 5 lipoproteinemia). In most cases, after the release of these patients from the state of severe alcoholic hyperlipidemia, the VLDL level remains somewhat elevated (type 4 lipoproteinemia), which indicates one of the forms of familial hypertriglyceridemia or multiple type hyperlipidemia, which intensifies and becomes type 5 under the influence of ethanol.

Ethanol increases plasma triglyceride levels primarily because it inhibits fatty acid oxidation and increases liver synthesis. Excess fatty acids are esterified into triglycerides. Some of the excess triglycerides accumulates in the liver, which causes its typical increase and fat overload ("alcoholic liver"). The rest of the generated triglycerides are released into the plasma, resulting in increased VLDL secretion. With the development of severe alcoholic hyperlipidemia, the catabolism of these particles is probably partially disturbed. As the concentration of VLDL increases, they begin to compete with chylomicrons for hydrolysis by lipoprotein lipase, so the concentration of chylomicrons in plasma also increases.

With severe alcoholic hyperlipidemia, eruptive xanthomas often appear and retinal lipemia develops. The most severe complication (pancreatitis) is sometimes difficult to diagnose because elevated triglyceride levels interfere with serum amylase detection. There is no evidence that pancreatitis may cause hyperlipidemia. Most likely, on the contrary, it is the cause of this serious complication.

Plasma of patients with alcoholic hyperlipidemia has a sweeping appearance. If a blood sample is taken in the presence of Ca-EDTA and the plasma is placed in a refrigerator overnight, then the chylomicrons float to the surface, and the layer under them remains cloudy due to the simultaneously increased level of VLDL and chylomicrons (type 5).

Oral contraceptives. Taking estrogen-containing contraceptives is accompanied by an increase in the rate of VLDL secretion by the liver. In most women, VLDL catabolism also increases, so the level of triglycerides in plasma increases moderately. However, in women with an initial genetic disorder (familial hypertriglyceridemia or multiple-type hyperlipidemia), the plasma VLDL triglycerides may increase very significantly, and hyperchylomicronemia develops when estrogen-containing drugs are taken. Their mild degree of hypertriglyceridemia is usually determined even before the start of oral contraceptive use and, probably, VLDL catabolism is not activated in response to the optimization of the production of these particles. An increase in the level of VLDL prevents the normal destruction of chylomicrons by lipoprotein lipase, therefore secondary hyperchylomicronemia develops. In these cases, severe pancreatitis can develop.

Taking oral contraceptives may be a risk factor for thromboembolic disease in young women, especially with preexisting hypercholesterolemia. Therefore, plasma cholesterol and triglyceride levels must be measured before starting contraception. Hyperlipidemia is a contraindication for taking them.

Rare disorders of lipid metabolism

Table 315-5 summarizes the clinical and pathophysiological features of five rare autosomal recessive disorders of lipid metabolism. With two of them (abetalipoproteinemia and Tangier disease), the underlying disorder is a decrease in plasma lipids. With the other two (cerebro-tendon xanthomatosis and sitosterolemia), a congenital defect causes the accumulation of unusual sterols in the tissues. In case of lecithin cholesterol acyltransferase (LCAT) deficiency, the initial mutation provokes a disruption in the structure of plasma lipoproteins and the accumulation of non-esterified cholesterol in the tissues.

Table 315-5. Rare autosomal recessive disorders of lipid metabolism

Hyperlipoproteinemia and other lipid metabolism disorders

Hyperlipoproteinemia and other lipid metabolism disorders. Part 3