DISTURBANCES OF LIPID METABOLISM

 CLASS № 27 

THEME: DISTURBANCES OF LIPID METABOLISM

1. Disorders in digestion and absorption of lipids in the gastrointestinal tract. 

2. Dislipoproteinemias: hyper- and hypolipoproteinemias.

3. Hypercholesterolemia and atherosclerosis. Biochemical principles of treatment. 

4. Cholelithiasis. Formation of cholesterol gall stones. 

5. Obesity: disturbances of lipid metabolism.

1. Disorders in digestion and absorption of lipids in the gastrointestinal tract.

Received dietary fats if their intake is moderate (no more than 100-150 g), are almost completely absorbed, and normal digestion feces contain no more than 5% fat. 

Remains of fatty food are allocated mainly in the form of soaps.

In case of disturbances of the digestion and absorption of lipids the excess of lipids in the stool, steatorrhea (fatty stools) is observed. 

There are 3 types of steatorrhea. 

01.Pancreatogenous steatorrhea occurs in case of pancreatic lipase deficiency. 

⦁ The reasons for such a state can be chronic pancreatitis, 

⦁ pancreatic inborn hypoplasia, 

⦁ congenital or acquired deficiency of pancreatic lipase, 

⦁ as well as cystic fibrosis, where the pancreas is damaged along with other glands. 

In this case, 

⦁ the feces contain bile pigments, 

⦁ reduced levels of free fatty acids 

⦁ and increased TAG. 

02.Hepatogenous steatorrhea is caused by blockage of the bile ducts. 

⦁ This occurs in congenital biliary atresia, 

⦁ resulting in narrowing of the bile duct by gallstones, or pinched tumor growing in the surrounding tissues. 

Decreasing the secretion of bile emulsification leads to disruption of dietary fat, and, consequently, blockage of their digestion. 

In the feces of patients there are no bile pigments, but high content of TAG, fatty acids and soaps can be found. 

03.Enterogenous steatorrhea 

is observed in 

⦁ intestinal lipodistrophy, 

⦁ amyloidosis, 

⦁ extensive resection of the small intestine, 

in processes accompanied by a decrease in metabolic activity of the intestinal mucosa. 

This pathology is characterized by fecal pH shift to the acid medium, the growth of fatty acids content in feces.

2. Dyslipoproteinemias: hyper- and hypolipoproteinemias.

Dyslipoproteinemia

All changes in PhL content in plasma (increase, decrease or complete absence) is called dyslipoproteinemia. 

Dyslipoproteinemia can be either a specific primary manifestation of disturbances in lipid and lipoprotein metabolism, 

a concomitant syndrome in some diseases of the internal organs (secondary dislipoproteinemia). 

With successful treatment of the underlying disease, they disappear. 

Hypolipoproteinaemias 

Hypolipoproteinaemias include the following conditions: 

1. Abetalipoproteinemia occurs as a rare inherited disorder – 

⦁ a defect of apoprotein B gene, when protein synthesis of apoB-100 in the liver and apoB-48 in the intestine is disrupted. 

⦁ As a result, in the cells of the intestinal mucosa ChM is not formed, 

⦁ while VLDL is not synthesized in the liver, 

⦁ and the cells of these organs accumulate fat droplets. 

2. Family hypobetalipoproteinemiya: 

⦁ concentration of PhL, 

⦁ containing apoB, is only 10-15% of normal levels, but the body is capable of forming ChM. 

3. Family insufficiency of alfa-LP (Tangier disease): 

in plasma HDL is almost not detectable, and large amounts of cholesterol esters are accumulated in the tissues.

The absence of apoС-II (activator of LPL) in patients leads to a characteristic increase in TAG concentration in plasma. 

There are following types of hyperlipoproteinemia: 

01. Type I – Hyperchylomicronemia. 

Removal rate of ChM from the bloodstream depends on LPL(Lipoprotein lipase) activity, the presence of HDL, supply of apoproteins C-II and E to ChM, activity of apoC-II and apoE transport on ChM. 

Genetic defects in any of the proteins involved in the metabolism of ChM, lead to the development of family hyperchylomicronemia – ChM accumulation in the blood. 

The disease manifests itself in early childhood, characterized by hepatosplenomegaly, pancreatitis, abdominal pains. 

Treatment: diet with a low lipid content (up to 30 g/ day) and high carbohydrate content. 

Type II – family hypercholesterolemia (hyper-betalipoproteinemia). 

This type is divided into two subtypes: 

⦁ IIa characterized by high blood levels of LDL and 

⦁ IIb – with elevated levels of both LDL and VLDL. 

The disease is associated with impaired reception and catabolism of LDL (defect of cellular receptors for LDL or change in the structure of LDL), 

accompanied by increased biosynthesis of cholesterol, apo-B and LDL. 

This is the most serious pathology in LP metabolism: 

⦁ the risk of coronary heart disease in patients with this type of violation increases 10-20 times compared with healthy individuals. 

As a secondary phenomenon hyperlipoproteinemia type II may develop hypothyroidism, nephrotic syndrome. 

Treatment: a diet low in cholesterol and saturated fat. 

Type III – dis-beta-lipoproteinemiya (broadband betalipoprotenemiya)

It occurs due to an anomalous composition of VLDL. 

They are rich in free cholesterol, but have a deficit of apo-E, inhibiting the activity of hepatic TAG lipase. 

This leads to violations of the catabolism of VLDL and XM. 

The disease manifests itself in the age of 30-50 years. 

The condition is characterized by high VLDL remnants, and hypercholesterolemia reveals by xanthoma and atherosclerotic lesions of peripheral and coronary vessels. 

Treatment: diet therapy aimed at weight reduction.

Type IV – hypertriacylglycerolemia. 

The primary form occurs due to a decrease in LPL activity, increased TAG in plasma. 

ChM accumulation is not observed. 

The state occurs only in adults and is characterized first by the development of atherosclerosis of coronary arteries, and then peripheral arteries. 

The disease is often accompanied by a decrease in glucose tolerance. 

Secondary form occurs in pancreatitis, alcoholism. 

Treatment: diet therapy aimed at reducing weight. 

Type V – mixed hyperlipoproteinemia familial. 

In this type of pathology changes in blood lipoprotein fractions are complex: content of ChM and VLDL fractions increases, LDL and HDL decreases severely. 

Patients often are overweight, may develop hepatosplenomegaly, pancreatitis. 

Atherosclerosis does not develop in all cases. 

As a secondary phenomenon hyperlipoproteinemia type V may occur with insulin dependent diabetes mellitus, hypothyroidism, pancreatitis, alcoholism, type I glycogen storage disease. 

Treatment: diet therapy aimed at reducing weight (a diet low in carbohydrates and fat).

4. Cholelithiasis. Formation of cholesterol gall stones. 

Cholelithiasis

Gallstone disease is a pathological process in which the gallbladder stones are formed. 

Secretion of cholesterol in the bile must be accompanied by a proportional allocation of bile acids and phospholipids, cholesterol retaining hydrophobic molecules in a micellar state. 

Causes leading to the change in the ratio of bile acids and cholesterol in bile are foods rich in cholesterol, high-calorie food, stagnation of bile in the gallbladder, violation of the enterohepatic circulation of bile acid synthesis disorders, gall bladder infection. 

Most patients with gallstone disease have increased synthesis of cholesterol, and synthesis of bile acids is slowed, which leads to a disruption of the amount of cholesterol and bile acids are secreted into the bile. 

As a result, cholesterol begins to precipitate in the gallbladder, forming a viscous precipitate which slowly solidifies. 

Sometimes it is impregnated by bilirubin, proteins and calcium salts. 

Stones can consist only of cholesterol (cholesterol stones) or a mixture of cholesterol, bilirubin, protein and calcium. 

Cholesterol stones are usually white, and mixed (different shades of brown). In the initial stage of stones formation chenodeoxycholic acid can be used as a medicine. 

Getting into the gallbladder, it gradually dissolves cholesterol stones, but it is a very slow process, lasting several months.

Conditions which Favour Stone Formation 
1. Infection favours stone formation. 
Infection causes: 
⦁ Deconjugation of bile acids leading to decrease in solubility. 
⦁ Production of phospholipase, which converts lecithin to lysolecithin. 
⦁ Thus, the ratio cholesterol/bile acids is disturbed leading to precipitation of cholesterol. 

2. Reduction in bile salt pool: 
⦁ Defect in enterohepatic circulation. 
⦁ Disease of terminal ileum. 
⦁ In patients with cirrhosis live

3. Hypercholesterolemia and atherosclerosis. Biochemical principles of treatment. 

Atherosclerosis is a pathology characterized by the appearance of atherogenic plaques on the inner surface of the vascular wall. 

One of the main causes of this disease is an imbalance between the supply of cholesterol from food, its synthesis and excretion from the body. 

In patients suffering from atherosclerosis, elevated concentrations of LDL and VLDL is observed. 

There is an inverse relationship between HDL cholesterol concentration and the likelihood of atherosclerosis. 

The basic metabolic reason of atherosclerosis development is hypercholesterolemia (high level of cholesterol in the blood). 

Hypercholesterolemia develops: 

⦁ due to excess income of cholesterol, carbohydrates and fats; 

⦁ due to genetic predisposition, genetic defects consisting in LDLreceptors or structures of apoB-100 as well as the increased synthesis or secretion of apoB-100 (in case of familial combined hyperlipidaemia, in which HDL and TAG concentration in the blood is increased). 

Important role in the mechanisms of atherosclerosis is played modification of LP. 

Changes in the normal structure of the lipid and protein composition in LDL make them foreign to the body, and therefore more accessible for gripping by phagocytes. 

Modification of LP may occur through several mechanisms: 

⦁ glycosylation of proteins occurs with increasing concentration of glucose in blood; 

⦁ peroxide modification, leading to changes in lipid and lipoprotein structure of apoB-100;

⦁ formation of autoimmune complexes (LP-antibody). 

Modified LP may cause the formation of autoantibodies. 

Modified LDL ingested by macrophages. 

This process is not regulated by the amount of cholesterol absorbed as if it enters cells via specific receptors, so macrophages become overloaded with cholesterol and turn into “foam cells” penetrating into the subendothelial space. 

This leads to the formation of lipid spots or strips in the wall of blood vessels. 

At this stage, the vascular endothelium can maintain its structure. 

The increase in the amount of foam cells leads to endothelium damage. 

This damage facilitates platelets activation. 

As a result, they secrete thromboxane, which stimulates platelet aggregation and platelet starts to produce a growth factor that stimulates the proliferation of smooth muscle cells. These cells migrate from the medial layer to the inner surface of the arterial wall, thus contributing to plaque growth. 

Further there is a germination of the fibrous tissue into a plaque, the cells necrotize under the fibrous sheath and cholesterol is deposited in the intercellular space of the arterial wall. 

In the late stages of development the plaque is impregnated with calcium salts and becomes very dense. 

In the plaques thrombi are often formed overlying the vessel lumen, leading to acute circulatory problems in the relevant section and myocardial tissue. 

Biochemical basis of atherosclerosis treatment. 

Important therapeutic factor that reduces the risk of hypercholesterolemia and atherosclerosis is hypocaloric and hypolipidemic diet. 

Daily cholesterol intake will not exceed 300 mg/day. 

Curative and preventive factors include food rich in polyene fatty acids, which reduce the risk of thrombosis and promote the excretion of cholesterol from the body. 

Vitamins C, E, A, antioxidant properties, inhibit lipid peroxidation, thereby maintaining normal structure and metabolism of LDL.

In this case, treatment of atherosclerosis is usually integrated.

One of the principles of treatment is breaking the cycle of the enterohepatic circulation of bile acids. 

For this purpose cholisteramin – a polymer which adsorbs bile acid in the intestine and is excreted with the faeces – reduces the bile acids returning to the liver. 

In the liver, it increases the capture of blood cholesterol for the synthesis of bile acids. 

The most effective drugs used in the treatment of atherosclerosis are inhibitors of HMG-CoA reductase. 

Such drugs can almost completely suppress the synthesis of cholesterol in the body. 

Under these circumstances the LDL flow from blood to the liver increases. 

Medications – fibrates – accelerate the catabolism of VLDL, activating LP lipase. 

These drugs also enhance the oxidation of fatty acids in the liver, thereby reducing the synthesis of cholesterol esters and TAG and, consequently, secretion of VLDL by the liver. 

Clofibrate induces the synthesis of enzymes of peroxisomes capable of oxidizing fatty acids. 

Fibrates are usually used in simultaneous gipertriglitserolemii and hypercholesterolemia. 

For effective treatment of atherosclerosis, usually, the combined effect of several drugs is used.

PATHOLOGICAL VARIATIONS OF SERUM CHOLESTEROL 

• Normal value: 3.6-5.2 mmol/L 

• Hypercholesterolemia: in nephrotic syndrome, diabetes mellitus, obstructive jaundice, myxoedema, xanthomatous biliary cirrhosis, hypopituitarism, xanthomatosis, coronary thrombosis and in angina pectoris. 

• Hypocholesterolemia: in thyrotoxicosis, anaemias, haemolytic jaundice, malabsorption syndrome, wasting diseases, acute infections and in a number of terminal states.

5. Obesity: disturbances of lipid metabolism.

A condition where the body weight by 20% is more than ideal for a given individual is considered obese. 

It develops when the adipose tissue processes of lipogenesis predominate. 

Adipocyte formation occurs in utero from the last trimester of pregnancy, and ends in the prepubertal period. 

After that fat cells can increase in size with obesity or decrease in weight loss, but their number does not change throughout the life. 

One classification of obesity is based on the size and number of adipocytes. 

The increase of total number of these cells indicates hyperplastic obesity (developing in infancy, hereditary). 

The enlarged size of adipocytes leads to hypertrophic obesity. 

According to another classification we can observe

⦁ Primary obesity 

⦁ secondary obesity 

Primary obesity develops as a result of nutritional imbalance, i.e. excessive caloric intake compared with the cost of energy. 

As a result 80% of cases are genetic disorders. 

Metabolic differences between obese and normal people can not be uniquely determined up to day. 

One of the supposed reasons for these differences is the fact that people who are prone to obesity have different ratio of aerobic and anaerobic glycolysis, the differences in the activity of Na+/K+-ATPase. 

Moreover, the scientist found out that humans and animals have the gene of obesity. 

The expression product of this gene is the protein leptin, which is synthesized and secreted by adipocytes and interacts with receptors in the hypothalamus. 

As a result, it decreases the secretion actions of neuropeptide Y, stimulating food intake.

Most of the patients with obesity have a genetic defect of leptin receptors in the hypothalamus. 

But as a result the secretion of the neuropeptide Y extends, which leads to an increase in appetite and consequently weight gain. 

Secondary obesity is the form of obesity that develops as a result of an illness, often endocrine one. 

For example, hypothyroidism, Cushing's syndrome and hypogonadism lead to the development of obesity.