Circulating Lipids & Lipoproteins
The major serum lipids include free (unesterified) fatty acids, lysophospholipids, triglycerides, cholesterol (70% esterified with fatty acids), and phospholipids. Lipids are insoluble in aqueous solution and are transported in plasma complexed with specific proteins or apoproteins. Free fatty acids and lysophospholipids are bound by albumin; triglycerides, cholesterol, cholesterol esters and phospholipids exist as large lipid-protein complexes called lipoproteins.

In normal fasting serum, there are three major classes of lipoproteins, which may be resolved by ultracentrifugation or electrophoresis. The lipoprotein classes are interchangibly designated on the basis of their electrophoretic (or corresponding ultracentrifugal) behavior as beta- (or LDL, low density), prebeta- (or VLDL, very low density) and alpha (or HDL, high density) lipoproteins.
For approximately two to eight hours following a meal there is an additional lipoprotein class, called chylomicrons, representing the transport of dietary fat absorbed in the intestine.

Pertinent properties of the lipoprotein classes are shown in the table below:

Laboratory Analyses

                                       "desireable"   "high risk"
                                         (mg/dl)       (mg/dl)

     *appearance of serum                 clear, straw colored
     (if lipemic, evaluate next day)

     cholesterol                         < 200        > 240

     LDL cholesterol (calculated:        < 130        > 160
      = tot. chol. - trig./5 - 45)

     HDL cholesterol                     >  60        <  35

     triglycerides                       < 200        > 300

*"Lipemic" appearance is associated with elevated VLDL (triglyceride >600 mg/dl) and/or the presence of chylomicrons (triglyceride >200 mg/dl).
The appearance of the undisturbed specimen the following day reflects elevated VLDL and/or the presence of chylomicrons:

homogeneously lipemic = increased VLDL

floating creamy layer     = chylomicrons

homogeneously lipemic & floating creamy layer = increased VLDL & chylomicrons

Clinical Significance of Serum Lipid Test Results

Elevations of Total Serum Cholesterol and/or Triglyceride

Lipid elevations are a consequence of one or a combination of the following:

dietary excess of fat and carbohydrate

genetic defects in lipoprotein metabolism

secondary to other disease.

Results from the Framingham Study, a summary of which is depicted to the right, demonstrated a significant relationship between serum cholesterol concentration and the occurrence of MI. Individuals with serum cholesterol concentrations within the upper half of the "normal range" are at a two - three fold greater risk of experiencing a myocardial or cerebral infarct as a consequence of serious atherosclerosis, than are individuals with serum cholesterol concentrations less than 225 mg/dl. Similar epidemiologic studies demonstrated that serum triglyceride concentration was also a risk factor for atherogenisis, though less significant than serum cholesterol. Conclusions from other, more recent, epidemiologic studies are in general agreement with the Framingham study.

HDL and LDL cholesterol:

Epidemiologic studies have also demonstrated that decreased HDL is associated with increased incidence of disease from atherosclerosis and increased HDL with decreased atherogenesis. In addition, many of the groups which are known to be at decreased risk (e.g., females, joggers, 2 cocktails/day, etc.) have increased HDL, whereas high risk groups (e.g., diabetics, smokers, etc.) have decreased HDL. It has been proposed that the protective effect of HDL is due to its metabolic role of removing and esterifying free cholesterol from tissues and from the circulation and ultimately presenting it to the liver, via transfer to other lipoproteins, for degradation and excretion into the bile.
Since LDL and HDL are independent risk factors, it is not surprising that their ratio serves as a single risk factor taking into account their combined, and opposite, effects. Since most of total cholesterol is represented by LDL, the total/HDL cholesterol ratio is considered just as good a risk factor as the LDL/HDL ratio.

Complete genetic deficiency of HDL (Tangier's disease) is associated with a very high risk for disease from atherosclerosis. Heterozygous, mild HDL deficiency is the metabolic defect in familial type IV hyperlipoproteinemia.

Brief Review of Lipid and Lipoprotein Metabolism

Digested lipids (average dietary intake is about 100 g of triglyceride and 0.5 g of cholesterol per day) are absorbed in the intestinal tract and triglycerides and phospholipids are resynthesized in intestinal epithelial cells. The lipids complex with apoproteins CII, B, and E and are transported in the thoracic lymph duct as chylomicrons. Chylomicrons slowly enter the circulation and are present in blood from about two to about eight hours following a meal. Triglycerides are hydrolyzed by lipoprotein lipase, present on the luminal surface of endothelial cells in muscle and adipose tissue. Triglyceride hydrolysis by lipoprotein lipase requires apoprotein CII, so that extracellular hydrolysis of triglycerides takes place only with chylomicrons and VLDL. Cholesterol and phospholipids from the triglyceride poor chylomicrons are transferred to HDL. The residual chylomicron remnants rapidly interact with hepatocyte membrane receptors for apoproteins B and E and are endocytized and hydrolyzed by lysosomal enzymes.

Primary Hyperlipoproteinemia

Primary hyperlipidemia is caused by excessive fat and/or carbohydrate ingestion and/or genetic defects of lipoprotein metabolism. Diagnosis and treatment of hyperlipidemia requires recognition of the responsible lipoprotein(s). Genetic lipoprotein abnormalities are classified into 5 (pheno) types and are generally readily diagnosed on the basis of the alterations in cholesterol and triglyceride concentrations and the appearance of the specimen. A genetic cause for hyperlipidemia can be established only from a family history.

Lipid profile results, total triglycerides, total cholesterol, HDL cholesterol and LDL cholesterol, reported by the laboratory often include interpretive classification of abnormal results in terms of one of the above hyperlipoproteinemia types. The most commonly found types in practice are IV, IIb and IIa.

Type IV is defined as elevated VLDL and is characterized by elevated triglycerides and normal LDL cholesterol. The specimen is usually lipemic when the triglyceride concentration is greater than about 600 mg/dl and the lipemia remains homogeneously distributed after the specimen stands undisturbed overnight.
The metabolic defect is (partial)HDL deficiency. (Tangier's disease is homozygous HDL deficiency.)

Type IIa is defined as elevated LDL and is characterized by elevated LDL cholesterol and normal triglycerides or triglycerides may be slightly elevated but total cholesterol/triglyceride is greater than 2.
The metabolic defect is deficiency of apoB receptors.

Type IIb is defined as elevated LDL and VLDL and is characterized by elevated LDL cholesterol and triglycerides with total cholesterol/triglyceride about 1 (0.7-1.5). Total triglyceride is generally less than 400 mg/dl.
The metabolic defect is a combination of that of Type IIa and Type IV.

Types I, III and V are rare.

Type I is defined as the presence of chylomicrons without an elevation of VLDL as evidenced by lipemia which after standing overnight forms a floating creamy layer over a clear infranate. Triglyceride is elevated and cholesterol is normal.
The metabolic defect is deficiency of lipoprotein lipase.

Type V is defined as the presence of chylomicrons and an elevation of VLDL as evidenced by lipemia which after standing overnight forms a floating creamy layer over a lipemic infranate. Triglyceride is elevated and cholesterol is normal or only slightly increased.
The metabolic defect is a combination of lipoprotein lipase and (partial)HDL deficiency.

Type III is defined as the presence of chylomicron remnants and/or IDL and is characterized by lipemia with elevated triglycerides and cholesterol and total cholesterol/triglyceride is about 1 (0.7-1.5). Type III can be definitively distinguished from Type IIb only by polyacrylamide (molecular sieving) electrophoresis in which Type III exhibits a single band in the slow VLDL position or by ultracentrifugation in which flotation more rapid than beta is exhibited.
The metabolic defect is defective apoE.

Summary of HyperLipoproteinemia Phenotypes

Type	metabolic defect	LP abnormality	predominant hyperlipidemia	appearance next day
I	deficient lipoprotein lipase	fasting chylomicrons	hypertriglyceridemia	floating creamy layer over clear serum
IIa	deficient apoB receptors	increased LDL	hypercholesterolemia	clear serum
IIb	deficient apoB receptors and deficient HDL	increased LDL	hypercholesterolemia hypertriglyceridemia	clear (if trig < 500 mg/dl) lipemic (if trig > 600 mg/dl)
III	defective apoE	increased IDL and chylomicron remnants	hypercholesterolemia hypertriglyceridemia	lipemic
IV	deficient HDL	increased VLDL	hypertriglyceridemia	clear (if trig < 500 mg/dl) lipemic (if trig > 600 mg/dl)
V	deficient lipoproteinlipase and deficient HDL	fasting chylomicrons and increased VLDL	hypertriglyceridemia	floating creamy layer over lipemic

Secondary Hyperlipidemia:

Secondary hyperlipidemia is a consequence of other disease:

• diabetes mellitus - when poorly controlled; from increased liver synthesis of VLDL because of increased liberation of free fatty acids from adipose tissue, and from increased LDL because of decreased tissue LDL receptors (one of the effects of insulin is to increase apo-B receptors) and consequent decreased degradation rate and increased rate of synthesis.
• hypothyroidism - from increased LDL because of decreased tissue LDL receptors (one of the effects of thyroid hormone is to increase apo-B receptors - in contrast, hyperthyroidism is often associated with low serum cholesterol).
• liver disease:
  • diminished hepatocellular function - deficient LCAT activity and decreased cholesterol esterification, resulting in the presence of an abnormal lipoprotein.
    
  • biliary obstruction - diminished biliary excretion of bile salts and cholesterol, resulting in the presence of an abnormal lipoprotein (lipoprotein X).
• the nephrotic syndrome - from the compensatory increase in hepatic synthesis of most proteins and the accumulation of large macromolecules, including VLDL and LDL, which are not filtered by the "leaky" glomeruli.