Medicine

Lipids and lipoproteins: metabolism and its violations

Lipids and lipoproteins: metabolism and its violations

 

 

LIPOPROTEIN METABOLISM

Lipoproteins are complexes of lipid and proteins which facilitate lipid transport. The lipoprotein system evolved to solve the problem of  transporting  fats around the body in the aqueous environment of the plasma. A lipoprotein is a complex spherical structure which has a hydrophobic core wrapped in  a hydrophilic coating.

The core contains triglyceride and cholesterol esters, while the surface contains phospholipids, free cholesterol and proteins - apolipo-proteins (Table 1). Cholesterol is an essential component of all cell membranes and is the  precursor  for steroid hormone and bile acid biosynthesis. Triglyceride is central to the storage and transport  of energy with in the body.

 

Table 1.  Properties of some human apolipoproteins

Apolipoprotein

Molecular weight

Site of synthesis

Function

A-I

28 000

Intestine, liver

Activates LCAT

A-II

17 000

Intestine, liver

-

B

549 000

Liver

Triglyceride and cholesterol transport

Binds to LDL receptor

B

264 000

Intestine

Triglyceride transport

C-I

6600

Liver

Activates LCAT

C-II

8850

Liver

Activates LPL

C-III

8800

Liver

Inhibits LPL

E

34 000

Intestine, liver, macrophage

Binds to LDL receptor and probably also to another specific liver receptor

 

LCAT – lecithin:cholesterol acyl transferase

LPL – lipoprotein lipase

 

 

NOMENCLATURE

Several different classes of lipoproteins exist whose structure and functions are closely related. Apart from the largest species, the chylomicron, these are named according to the density, as they are most commonly isolated by ultracentrifugation. The four main lipoproteins and their functions are shown in the Table 2.

 

 

Table 2. The four main lipoproteins and their functions

 

Lipoprotein

Main apolipoproteins

Function

Chylomicrons

B, A-I, C-II, E

Largest lipoprotein. Synthesized by gut after a meal. Not present in normal fasting plasma Main carrier of dietary triglyceride

Very low dencity lipoproteins (VLDL)

B, C-II, E

Synthesized in the liver. Main carrier of endogenously produced triglyceride

Low dencity lipoproteins (LDL)

B

Generated from VLDL in the circulation.

High dencity lipoproteins (HDL)

A-I,  A-II

Main carrier of cholesterol

 

 

METABOLISM

Lipoprotein metabolism can be thought of as two cycles, one exogenous and one endogenous, both are centered in the liver. These cycles are interconnected.

The two  key enzyme systems involved in lipoprotein metabolism, e.g:

1.     Lipoprotein lipase (LPL) releases free fatty acids and glycerol from chylomicrons and VLDL into the tissues.

2.     Lecithin :cholesterol acyl transferase (LCAT) forms cholesteryl esters from free cholesterol and fatty acids.

 

The exogenous lipid cycle

 

Dietary lipid is absorbed in the small intestine and incorporated into chylomicrons which are secreted into the lymphatics and reach the bloodstream via the thoracic duct. In the circulation, triglyceride is gradually removed from these lipoproteins by the action of lipoprotein lipase. This enzyme is present in the capillaries of number of tissues, predominantly in the adipose tissue and skeletal muscle. As it loses triglyceride, the  chylomicron  becomes smaller and deflated, with folds of redundant surface material. These reminents are removed by the liver to form cell membrane components or bile acids or may be excreted in the bile. The liver is the only route by which cholesterol leaves the body in significant amounts.

 

 

 

 

THE ENDOGENOUS lipid CYCLE

 

The liver synthesizes VLDL particles which undergo the same form of delipidation as chylomicrons  by the action of lipoprotein lipase. This results in the formation of an intermediate density lipoprotein (IDL) which becomes (LDL)when further delipidation.LDL may be removed from the circulation by the high affinity LDL receptors or by the other scavenger routes which are thought to be the important at high LDL levels and the main way in which cholesterol is incorporated into atheromatous plaques. HDL particles are derived from both liver and gut. They act as cholesterol ester shuttles, removing the sterols from the peripheral tissues and returning it to the liver. The HDL is taken up either directly by the liver or other circulating lipoproteins, which then return it to the liver. This process is thought to be anti-atherogenic, and  an elevated HDL –cholesterol level has been shown to confer a decreased risk of coronary heart disease on an individual.

 

 

Dyslipidemia and Lipoproteins

Lipoproteins are water-soluble spheres that transport lipids through the body. They are classified by their size, function and content of proteins, triglycerides, cholesterol and phospholipids. There are dozens of subtypes of lipoproteins, but only three are routinely monitored:

1)    very low density lipoprotein (VLDL)

2)    low density lipoprotein (LDL); and

3)    high density lipoprotein (HDL) (see TABLE 1).

Total cholesterol is the combination of VLDL, LDL and HDL, using the formula:
Total cholesterol = HDL + LDL + (VLDL/5)

 

 

 

 

 

APOLIPOPROTEINS

Apolipoproteins are the protein components of the lipoproteins (Table1). They are important in:

1. Maintaining the structural integrity of the lipoproteins

2. Regulating certain enzymes which act on lipoproteins

3. Receptor recognition

 

 

THE  LDL RECEPTOR 

The LDL receptor (Fig. 3), a glycoprotein present on the surface of all the cells, spans the cell membrane and is concentrated in a special membrane recesses, called ‘coated pits’. It binds to lipoprotein containing apolipoprotein B and E, and internalizes them for breakdown within the cell.   Receptors are then recycled to the cell surface. The number and function of receptors dictate the level of circulating LDL. When the cell has sufficient cholesterol, the synthesis of the receptors is down –regulated, when the cell is cholesterol depleted, the receptors increase in number. Inherited malfunction or absence of these receptors leads to familial hypercholesterolemia (FH).

     A specific malfunction of apolipoprotein B results in defective binding of LDL to its receptor and produces an identical clinical picture to FH called familial defective apoB (FDB).

 

 

 

CLINICAL DISORDERS OF LIPID METABOLISM

Lipoprotein  disorders are some of the commonest metabolic diseases seen  in clinical practice. They may present with their various sequelae which include:

1. Coronary heart disease (CHD)

2. Acute pancreatitis.

3. Failure to thrive and weakness.

4. Cataracts.

 

CLASSIFICATION

Currently there is no satisfactory comprehensive classification of lipoprotein disoders. Genetic classifications have been attemped but are becoming increasingly complex as different mutations are discovered (Table 3).

 

Table 3.  Some genetic causes of dyslipidaemia

 

Disease

Genetic defect

Fredrickson

Risk

Familial hypercholesteroleia

Reduced numbers of functional LDL receptors

IIa or IIb

CHD

Familial hypertriglyceridemia

Possibly single gene defect

IV orV

 

Familial combinrd hyperlipidemia

Possibly single gene defect

IIa or IIb,  IV orV

CHD

Lipoprotein lipase deficiency

Reduced levels of functional LPL

I

Pancreatitis

Apo C-II deficiency

Inability to synthesize Apo C-II(cofactor for lipoprotein lipase)

I

Pancreatitis

Abetalipoproteinemia

Inability to synthesize Apo B

Normal

Fat soluble vitamin deficiencies, neurological deficit

Analphalipoproteinemia

(Tangier disease)

Inability to synthesize Apo A

Normal

Neurological deficit, Cholesterol ester storage in abnormal sites

 

Familial hypercholesterolemia (FH) which presents with xanthelasma, tendon xanthomas, severe hypercholesterolaemia  and premature coronary heart disease may be due to any of over 150 different mutations  of the LDL  receptor gene. Mutations of the apolipoprotein (apo) B gene can give an identical syndrome. Familial  hyperchylomicronaemia which presents with recurrent abdominal pain and pancreatitis may result from genetic mutations of the lipoprotein lipase or apo C-II genes. Eruptive xanthomas are characteristic of hypertriglyceridaemia.

Until gene therapy and/or specific substitution therapy become more available, genetic classifications, which biologically very illuminating, are  unlikely to prove very useful in practice. 

 

In practice, lipoprotein  disorders are simplistically classified as being:

1.     Primary- when the disorder is not due to an identifiable underlying disease.

2.     Secondary- when the disorder is a manifestation of some other disease.

 

Primary.   The Fredrickson or World Health Organization classification is the most widely accepted for the primary hyperlipidaemias. It relies on the findings of plasma analysis, rather than genetics defect may fall into different groups, or may change grouping as the disease progresses or is treated. The major advantage of this classification is that it is widely accepted and gives some guidance for treatment. The  six types of hyperlipoproteinaemia defined in the Fredricson classification are not equally common. Types I and V are rare, while types IIa, IIb and IV are very common. Type III hyperlipoproteinaemia , also known as familial dysbetalipoproteinaemia, is intermediate in frequency, occurring in about  1/5000 of the population.

 

     Secondary. Secondary hyperlipoproteinemia is a well-recognized feature of a number of diseases (Table 4) which divide broadly into two categories:

-         Clinically obvious diseases such as renal failure, nephrotic syndrome and cirrhosis of the liver.

-         Covert conditions which may present as hyperlipidemia. These include hypothyroidism, diabetes mellitus and alcohol abuse.

 

 

 

 

 

 

 

Table 4. Common causes of secondary hyperlipidaemia

 

Disease

Usual dominant lipid abnormality

Diabetes mellitus

Increased  triglyceride

Alcohol excess

Increased triglyceride

Chronic renal failure

Increased triglyceride

Drugs, e.g. thiazide diuretics, non-selective  β-blockers

Increased triglyceride

Hypothyroidism

Increased cholesterol

Nephrotic syndrome

Increased cholesterol

 

Atherogenic profiles

The casual association of certain forms of hyperlipidemia and CHD is clearly the major stimulus for the measurement of plasma lipids and lipoproteins in clinical practice. The most common lipid disorder linked with atherogenesis and an increased risk of CHD is an elevated plasma LDL cholesterol level, but increasingly it is being recognized that individuals with low plasma HDL cholesterol and hypertriglyceridaemia are also at increased risk.

 

MANAGEMENT OF HYPERLIPIDEMIA

The management of hyperlipidemia  is an important aspect of coronary heart disease (CHD) risk factor correction. Modifying hyperlipidemia together with the other non-lipid risk factor has been repeatedly shown to delay or even reverse the progression of establishment CHD. Risk factors for CHD fall into two groups: those which can be corrected (such as smoking, hypertension, hyperlipidemia and obesity) and those which can not be influenced (such as age, sex and family history).

 

Table 5.  Coronary heart disease risk factors

Correctable

Non-correctable

Smoking

Age

Hyperlipidemia           

Sex

 

Hypertension

Family history of premature CHD

Obesity

Personal history of CHD

Lack of Exercise          

Diabetes  Mellitus

 

Excess Alcohol

 

 

 

Classification

Because the management of primary and secondary hyperlipidemia is fundamentally different the two groups of condition must be distinguished. The main secondary hyperlipidemias are due to:

1. Diabetes mellitus

2. Alcohol misuse

3. Hypothyroidism

4. Nephrotic syndrome.

 

MANAGEMENT GUIDELINES

 There have been many published strategies for the management of a patient with hyperlipidemia, most modern guidelines advocate the overall CHD risk assesment of a patient when deciding to treat hyperlipidemia. One tool for this assesment it shown in Figure. 

Here, knowledge of patient’s sex, age, smoking status, blood culture, diabetic status and total: HDL cholesterol ratio are integrated into a single score represented as the % risk of a major cardiovascular event over the next 5 years.

     From this strategy it is clear that the decision to treat  hyperlipidemia relies  heavily on the biochemical results. The interpretation of these results and the action limits used for intervention are based on data from large studies where standardized methods are used to measure plasma cholesterol, trigylceride and HDL cholesterol (HDL-C). It is therefore necessary that the laboratory analyzing the specimens follows strict quality control procedures, thus ensuring the high level of accuracy and precision . Because of gender differences in the incidence of CHD, most guidelines, including those in figure, have different strategies for men and women.

 

 

DIETARY MANAGEMENT

The first-line management of any primary hyperlipidemia should always be  dietary modification. This may be time consuming and difficult but its important  not to be underestimated. Dietary management as a sole therapy should be pursued for 3-6 months before its effect is evaluated. The principal dietary guidelines for educing both plasma cholesterol and triglyceride are shown in figure:

 

 

 

This diagram shows  the standard lipid-lowering dietary guidelines which are currently recommended, but these obviously require some translation for patient use. In the  essence, it is recommended that red meat and dairy consumption be reduced while that of vegetables, fruits and pulses be increased together with more fish (especially oily fish such as mackerel, salmon and tuna ). In addition to modifying  the composition of the diet, weight coupled with exercise are important as these will frequently  improve glucose  tolerance and lower blood pressure in addition to their effects on plasma lipids.

 

Drug therapy

 

Drug therapy for hyperlipidemia, if required should be viewed  as an adjust to dietary management and other lifestyle changes. There is currently a range of lipid-lowering drugs available with a variety of actions (Table 6). The commonest drugs for the treatment of primary  hypercholesterolaemia are the HMG CoA reductase inhibitors (the statins). Two statins, pravastain and simvastatin, have been conclusively shown to reduce coronary morbidity and mortality as well as all-cause mortality in large randomized controlled trials. The commonest drugs for the treatment of primary hypertriglyceridemia or combined hyperlipidemia are the fibrates.

 

 

Table 6. Lipid-lowering drugs

 

Drug group

Principal actions

Bile acid sequesting resins

Block bile acid reabsorption and lower total and LDL cholesterol

HMG CoA reductase inhibitors

Inhibit cholesterol biosynthesis and lower total and LDL cholesterol

Fibrates

Activate lipoprotein lipase and lower triglyceride, total and LDL cholesterol. May increase HDL cholesterol.

 

Atherosclerosis

Atherosclerosis is a type of arteriosclerosis. The name comes from the Greek words athero (meaning gruel or paste) and sclerosis (hardness). It's the term for the process of fatty substances, cholesterol, cellular waste products, calcium and fibrin (a clotting material in the blood) building up in the inner lining of an artery. The buildup that results is called plaque.

Arteriosclerosis is a general term for the thickening and hardening of arteries. Some hardening of arteries normally occurs when people grow older.

Plaque may partially or totally block the blood's flow through an artery. Two things that can happen where plaque occurs are:

·         There may be bleeding (hemorrhage) into the plaque.

·         A blood clot (thrombus) may form on the plaque's surface.

If either of these occurs and blocks the whole artery, a heart attack or stroke may result.

Atherosclerosis affects large and medium-sized arteries. The type of artery and where the plaque develops varies with each person.

Atherosclerosis is a slow, progressive disease that may start in childhood. In some people this disease progresses rapidly in their third decade. In others it doesn't become threatening until they're in their 50s or 60s.

Exactly how atherosclerosis begins or what causes it isn't known, but some theories have been proposed. Many scientists think atherosclerosis starts because the innermost layer of the artery becomes damaged. This layer is called the endothelium. Three possible causes of damage to the arterial wall are:

·         Elevated levels of cholesterol and triglyceride in the blood

·         High blood pressure

·         Cigarette smoke

Cigarette smoke greatly aggravates and speeds up the growth of atherosclerosis in the coronary arteries, the aorta and the arteries of the legs.

Because of the damage, over time fats, cholesterol, platelets, cellular debris and calcium are deposited in the artery wall. These substances may stimulate the cells of the artery wall to produce still other substances. This results in more cells accumulating in the innermost layer of the artery wall where the atherosclerotic lesions form. These cells accumulate, and many of them divide. At the same time, fat builds up within and around these cells. They also form connective tissue.

The innermost layer of the artery becomes markedly thickened by these accumulating cells and surrounding material. If the wall is thickened sufficiently, the diameter of the artery will be reduced and less blood will flow, thus decreasing the oxygen supply.

Often a blood clot forms and blocks the artery, stopping the flow of blood. If the oxygen supply to the heart muscle is reduced, a heart attack can occur. If the oxygen supply to the brain is cut off, a stroke can occur. And if the oxygen supply to the extremities occurs, gangrene can result.

Obesity

Obesity is characterized by excessive accumulation of body fat .

Obesity in not a condition for which a precise definition is particularly useful. Unlike many “real” diseases, obesity represents one arm of distribution curve of body fat or body weight, with no sharp cut-off point. Its importance lies in the many, often serious, complications to which obese people are subject. In these complications that warrant undertaking a treatment that is so often unsuccessful.

Exams and tests generally include:

·         Taking health history. doctor may review weight history, weight-loss efforts, exercise habits, eating patterns, what other conditions could be, medications, stress levels and other issues about health. Doctor may also review family's health history to see if there may be predisposed to certain conditions.

·         Checking for other health problems. If there are known health problems, it needs to be evaluated. It’s necessary also check for other possible health problems in the examination and laboratory tests, such as high blood pressure and diabetes.

·         Calculating your BMI. Check body mass index (BMI) to determine level of obesity. BMI also helps determine overall health risk and what treatment may be appropriate.

·         Measuring your waist circumference. Fat stored around waist, sometimes called visceral fat or abdominal fat, may further increase risk of diseases such as diabetes and heart disease. Women with a waist measurement (circumference) of more than 35 inches and men with a waist measurement of more than 40 inches may have more health risks than do people with smaller waist measurements.

·         A general physical exam. This includes measuring of height, checking vital signs, such as heart rate, blood pressure and temperature, listening to heart and lungs, and examining of abdomen.

·         Blood tests. They may include a cholesterol test, liver function tests, fasting glucose, a thyroid test and others, depending on health situation. It could be also recommend certain heart tests, such as an electrocardiogram.

 

Classification due to stages of obesity

A.   According to Brock’s index (N: weight = height – 100).

I.                   Weight excess < 30 %.

II.                Weight excess 30 – 50 %.

III.             Weight excess 50 – 100 %.

IV.            Weight excess > 100 %.

B.   According to Kettle’s index or body mass index .

 

 

 Experts believe that a person's body mass index (BMI) is the most accurate measurement of body fat for children and adults.

Adults with a BMI greater than 30 are considered obese. Adults with a BMI between 25 and 29.9 are considered overweight.

Overweight-27,5 – 29,9

I. 30,0 – 34,9

II. 35,0 – 39,9

III. > 40,0

 

 

Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes.[1] Some studies have shown the prevalence in the USA to be an estimated 25% of the population [2], and prevalence increases with age.

Metabolic syndrome is also known as metabolic syndrome X, cardiometabolic syndrome, syndrome X, insulin resistance syndrome, Reaven's syndrome (named for Gerald Reaven), and CHAOS (in Australia).[3]

Symptoms and features are:

·         Fasting hyperglycemiadiabetes mellitus type 2 or impaired fasting glucose, impaired glucose tolerance, or insulin resistance

·         High blood pressure

·         Central obesity (also known as visceral, male-pattern or apple-shaped adiposity), overweight with fat deposits mainly around the waist

·         Decreased HDL cholesterol

·         Elevated triglycerides

Associated diseases and signs are: hyperuricemia, fatty liver (especially in concurrent obesity) progressing to NAFLD, polycystic ovarian syndrome (in women), and acanthosis nigricans.

 

Acute coronary syndromes

Acute coronary syndromes (ACS) include “a broad spectrum of clinical presentations, spanning ST-segment-elevation myocardial infarction, through to an accelerated pattern of angina without evidence of myonecrosis”.

 

New acute coronary syndromes terminology and implications for diagnosis

The terminology used to describe ACS continues to evolve, with the emergence of the term “non-ST-segment-elevation acute coronary syndrome” (NSTEACS). This reflects a shift away from establishing a definitive diagnosis at presentation, and towards a more clinically appropriate strategy of forming a rapid working diagnosis with its implications for initial clinical decision making.

At presentation, the initial diagnostic nomenclature focuses on risk stratification to direct treatment strategies. Establishing a definitive diagnosis often requires time, particularly for evidence of myocardial necrosis to emerge, and has important implications pertaining to prognosis, diagnostic coding, and social issues such as insurance and licensure.

 

 

1 Defining acute coronary syndromes over time: presentation to final diagnosis