Patozone

Introduction

 

Type I: Hyperchylomicronemia

Type II: Hyperbeta-lipoproteinemia

Type III: Dysbeta-lipoproteinemia

Type IIb / IV: Familial Combined Hyperlipidemia

Type V: Mixed type lipoproteinemia

 

Familial hyperalphalipoproteinemia

Hypoalpha-lipoproteinemia

Anaplha-lipoproteinemia (Tangier disease)

Hypobeta-lipoproteinemia

Abeta-lipoproteinemia

Introduction

 

RR studies for cholesterol established

250 – 280 mg/dL

40 – 50% develop CHD

National Cholesterol Education Program Adult Treatment Panel III (ATPIII)

All adults (20 yrs and older) have fasting lipid profile every 5 years

Total cholesterol (TC) - High >240; Desire <200

Triglycerides (Tgs) - see below

LDLc - High 160-189; Desire <100

HDLc - Low <40, High > 60

 

NCEP guidelines (triglycerides)

Upper limit of normal 150 mg/dL

Borderline = 150 – 199 mg/dL

High = 200 – 499 mg/dL

Very high = ≥500 mg/dL

 

Apo-A

A-I –primary protein component of HDL

- activates LCAT: HDL receptor binding to allow

cholesterol extraction from cells

 

A-II –not athero-protective

 

Apo-B

Several forms in circulation

Key risk factor for developing atherosclerosis

 

B48 - found in chylomicrons; provides structural support

 

B100 - found in LDL and VLDL; Structural support; receptor binding to deliver cholesterol to target cells; feedback inhibition of liver cholesterol synthesis

 

Apo-C

Required for the metabolism of chylomicronsand VLDL

 

CII - found in chylomicrons, VLDL; early (nascent) HDL molecules; activates lipoprotein lipase

 

Apo-E

Found in Chylomicrons, VLDL, IDL; some HDL molecules; Receptor binding to clear lipoprotein remnants from circulation

- Varying genotypes influence cholesterol level

- MC is ApoE3

- ApoE4 high binding, high LDL, also linked to Alzheimer dz

- ApoE2 low binding, causes high IDL (famlial dyslipidemia typie III)

 

Apoprotein (a)

Binds to LDL; homology with plasminogen; may

inhibit clot lysis, facilitate cholesterol uptake by

scavenger receptors

 

Cholesterol

Synthesis in liver stimulated by free fatty acids, esp unsaturated fatty acids;

- dietary intake minor factor affecting cholesterol levels.

- cholesterol synthesis begins with acetyl CoA, and HMG-CoA reductase is rate limiting step (inhibited by the various statins)

- Cholesterol is needed for membrane structure

and for steroid hormone synthesis.

 

Lab: measured using cholesterol oxidase enzyme

 

Triglycerides

come from diet and liver synthesis

- triglycerides must be cleaved (by lipases, including lipoprotein lipase in tissue) to free fatty acids and glycerol in order to across cell membranes

- important as energy stores; when insulin and/or glucose levels are low, triglycerides are cleaved and free fatty acids are used for energy

 

Lab: after cleavage by lipase, glycerol measured in one of several ways (MC uses glycerol kinase to produce glycerol-3- phosphate, which is eventually metabolized by other enzymes to produce NADH)

- may be overestimated by endogenous sources of glycerol

 

Chylomicrons

 

Made exclusively in intestine

 

Contain cholesterol, triglycerides and specific apolipoproteins (B-48, A-1, C, E)

*** Bust 48 chylomicrons out of the gut!!!***

***E = Empty into liver***

Function: to transport dietary triglycerides

 

Not found in the blood of healthy people

 

If present, serum is turbid or milky

 

Floats on top of serum upon standing and refrigeration

 

Appear at application point (origin) on electrophoreis

 

 

Very Low Density Lipoprotein (VLDL)

 

Composed mostly of triglyceride

52% triglyceride, 22% cholesterol, 18% phospholipid, 8% protein

- migrates to pre-B region of electrophoresis

Two sources:

Dietary –exogenous triglycerides

Hepatic –endogenous triglycerides

 

Apo-C is the major apoprotein, also has B-100 and E

Not considered atherogenic

Caution: Triglyceride values above 200 mg/dl

Turbid serum a quick and dirty test for evaluation

 

 

Low Density Lipoprotein (LDL)

 

Forms through catabolism of VLDL

 

Friedwald equation

LDL = total cholesterol - HDL - TG/5

 

Delivers cholesterol to liver or other tissues where it is stored, deposited, or excreted

 

Composed of 80% lipid and 20% protein

 

Apo-B-100 is the major apoprotein

- migrates to B area on electrophoresis

Considered the major atherogenic lipoprotein

 

Two classes exist based on flotation density:

LDL 1 –more lipid rich

LDL 2 –more dense

 

Small dense fractions indicate high risk for CHD

 

Labs: MC calculation uses Friedewald equation:

LDL-C = Total Cholesterol – HDL-C – (Triglycerides/5)

- the term TG/5 estimates the VLDL cholesterol, and assumes that no chylomicrons are present, so need a fasting specimen

 

High Density Lipoprotein (HDL)

 

Major role is to esterifycholesterol

Many subfractions

HDL2 –

- high levels associated with longevity

- Low levels associated with CHD

 

HDL3 –associated with severity of CHD

 

Therapeutic agent in reducing atherosclerotic CVD

 

Labs: recently, “direct HDL-C” methods available using abs to apo B and apo E

- inaccurate with high triglycerides

 

Intermediate Density Lipoprotein (IDL)

 

Density characteristic of VLDL

 

Associated with “broad-βdisease”

 

Very atherogenic lipoprotein

 

Not seen in normal individuals

 

 

 

Lp(a)

 

 

Composed mostly of Apo-B

 

Plays a role in thrombogenesis

 

Plays a role in atherogenesis

 

Associated with elevated risk for CHD

 

Elevations often seen in

 

Levels can only be lowered with nicotinic acid

 

 

Type IIb or Type IV: Familial Combined Hyperlipidemia

 

Sx: Familial combined hyperlipidemia has been previously classified as type IIb or type IV hyperlipidemia but appears to constitute a specific subgroup. It is, in fact, probably the most common lipoprotein disturbance encountered in clinical practice, affecting possibly 30% of patients who survive myocardial infarction.

 

- Present with either an increase in LDL or VLDL or both, and in some patients the phenotypical expression may fluctuate depending on diet, alcohol exercise, and body weight. Although cholesterol and Apo B invariably remain elevated, the triglyceride (VLDL) fluctuation may make the diagnostic differentiation from secondary causes problematic

 

Sx: The major diagnostic feature of familial combined hyperlipidemia is an elevation of Apo B, which is often disproportionate to the cholesterol or LDL-C elevation. Most typically, total cholesterol and triglyceride levels are increased, with the total cholesterol in the 200 to 300 mg/dL range and triglyceride in the 200 to 500 mg/dL range. HDL-C level is often low

 

Familial combined hyperlipidemia is probably the result of excess hepatic lipoprotein production, with only minimal impairment of catabolic processes for

VLDL remodeling and LDL clearance

 

 

Type V: Mixed Lipoproteinemia

 

likely to be secondary to one of a number of

other disease states. Also, in a given patient, the disorder can fluctuate between type IV and V, which essentially demonstrates the absence or presence of concomitant chylomicronemia superimposed on a marked increase of VLDL values. Neither the exact genetic mechanism for familial type V disorder nor its genetic relationship to familial type IV disorder is understood.

 

Mech: characterized by elevation of triglyceride levels due to increases in both VLDL and chylomicrons. The increase in chylomicrons can be seen as a creamy surface layer when a plasma specimen is allowed to stand for 16 hours at 4 °C. The turbid to lactescent layer below the surface layer is a result of the VLDL increase. Plasma cholesterol level may be slightly to moderately increase. LDL-C and HDL-C levels are usually normal to low. In some patients, reduction of LPL has been reported.

 

The presence of circulating chylomicrons and VLDL in fasting plasma indicates that normal clearing mechanisms for triglyceride-rich lipoproteins are inadequate. Postheparin LPL activity is usually normal, which suggests that the defect is not

the same as in type I hyperlipoproteinemia

 

 

Familial Hyperalphalipoproteinemia

 

It appears to be transmitted as an autosomal dominant trait associated with a less than average cardiovascular disease risk.

 

Longevity analyses demonstrate an 8- to 12-year prolongation of life expectancy for kindred members. Myocardial infarction morbidity and

mortality are reduced.

 

Secondary hyperalphalipoproteinemia associated with use of estrogenic preparations or alcohol has been described. Elevated HDL-C levels are rarely the

result of estrogen, oral contraceptive, or excessive alcohol intake, but these factors must be ruled out

 

Distinctive primary elevations of HDL-C levels, slight elevation of total cholesterol level, and normal triglyceride concentrations characterize the syndrome.

Apo A-I is massively increased and are responsible for protection against atherosclerosis. HDL particles containing Apo A-I and Apo A-II.

 

To avoid a diagnosis of hypercholesterolemia based on total cholesterol values, HDL-C levels should routinely be measured whenever patients' lipid and

lipoprotein levels are assessed. In assigning risk and making therapeutic decisions, a level of 35 mg/dL is the currently recommended cut-off point

 

No hypothesis for the increased HDL levels found in familial hyperalphalipoproteinemia has been set forth. Although it may be associated with enhanced triglyceride-rich lipoprotein clearance and LPL activity, it is more likely to be due to increased Apo A-I synthesis

 

 

Hypoalpha-lipoproteinemia

 

Studies have shown a significant increase in atherosclerosis risk in persons with low HDL-C levels. Because the differences in HDL-C levels between various risk groups are small (5 -10 mg/dL), HDL-C measurements may be replaced by other measurements of the HDL moiety, such as measurement of Apo A-I.

 

A number of underlying disease states or environmental influences may be associated with reduced levels of HDL; one of the most common is hypertriglyceridemia. A number of studies have suggested that familial hypo-alphalipoproteinemia follows Mendelian dominant transmission

 

Ingestion of certain drugs, lack of exercise, obesity, and alcohol consumption are factors that interact with the underlying genetic pattern controlling HDL levels. Identification of individuals with familial hypoalphalipoproteinemia is important in the treatment of other associated risk factors. The underlying defect appears to be in the primary structure of Apo A-I. In another disorder, known as fish-eye disease, HDL levels are reduced to approximately 10% of normal, with an increase in triglyceride levels. Severe corneal opacity is noted clinically. Although the HDL levels are diminished, their apolipoprotein composition appears normal. Atherosclerosis is present in some patients, but it is usually a late manifestation.

 

Analpha-lipoproteinemia (Tangier disease)

 

The best-known disorder of HDL metabolism is Tangier disease. This rare autosomal recessive disorder is characterized by accumulation of cholesterol esters in the reticuloendothelial system and in other tissues. The disorder is associated with the virtual absence of HDL in plasma. Homozygous persons have undetectable amounts of HDL-C and extremely low levels of Apo A-I and A-II. Plasma total and LDL-C concentrations are usually low, and mild hypertriglyceridemia is often observed. The disorder is relatively benign because the lipid accumulation in the reticuloendothelial tissue does not usually affect any organ function. Unlike findings in LDL abnormalities, the abnormality in Tangier disease is predominantly cerebrovascular in character.

 

Hypobeta-lipoproteinemia

 

more common than previously suspected, probably because of the limited attention focused on the persons in the lower fifth percentile of plasma total cholesterol and LDL-C level distributions. Familial hypobetalipoproteinemia is inherited as an autosomal dominant trait. Like increased HDL-C, reduced plasma LDL-C concentration is associated with significant increases in life expectancy in both men and women, which is probably related to relative diminution myocardial infarctions.

 

The syndrome is arbitrarily defined as an LDL-C level below the fifth percentile for a given sex- and age-matched population. The condition should not be confu-sed with abetalipoproteinemia. In hypobetalipoproteinemia, LDL-C is always detectable, whereas levels of other lipoproteins such as VLDL and HDL may be, low, normal, or even increased.

 

Studies suggest that these patients synthesize LDL at only half the normal rate, but that the catabolic rate remains normal. Because LDL is the breakdown product VLDL, patients also have low triglyceride values

 

 

Abeta-lipoproteinemia

 

A rare autosomal recessive disorder characterized by absence of lipoprotein species containing Apo B. This is manifested in the total absence LDL with consequent very low plasma levels of total cholesterol. Persons who are heterozygous for the disorder have no known clinical or biochemical abnormality but may present with hypobetalipoproteinemia. Persons who are homozygous have no detectable chylomicrons, VLDL, or LDL; therefore, levels of triglyceride, cholesterol, and phospholipids are extremely low. Total plasma cholesterol concentrations are usually less than 50 mg/dL, and virtually all of the total plasma cholesterol is associated with HDL. All of the other apolipoproteins, A-I, A-II, and the C series, are usually present

 

Sx: Malabsorption of dietary fat causes poor weight gain and failure to thrive. Steatorrhea occurs in patients who continue to take in a normal-fat diet. Malabsorption of fat is associated with severe malabsorption of fat-soluble vitamins. Without vitamin E administration in a water-soluble form, patients suffer progressive degeneration of the central nervous system. Another abnormality, probably caused by the lack of carotene and vitamin A, is decreased visual acuity and night blindness. Blood smears from many affected patients show spiny projections called acanthocytes (i.e., "thorn" or "spur" cells) on 50% to 70% of erythrocytes. Prothrombin time may also be prolonged as a result of vitamin K malabsorption

 

Mech: The exact underlying biochemical defect involves an abnormality in the synthesis or secretion of the lipoproteins containing Apo B. The result is severe malabsorption of fat due to failure of chylomicron formation and the restricted delivery of endogenously synthesized cholesterol to peripheral tissue via the LDL pathway.