Hyperlipoproteinemia type V

Algorithms based on cholesterol test results can assess the degree of risk for coronary heart disease and prescribe preventive treatment.

As one health care firm advertised to consumers last year, "Life is not a dress rehearsal. . . . Prevention really is the best medicine." Reflecting these sentiments, major health care providers and the American public are taking a close look at ways to prevent myocardial infarction, the leading cause of death in the United States.

Monitoring blood cholesterol is a central element in this effort. There is overwhelming evidence that lowering blood cholesterol decreases the mortality and morbidity of coronary heart disease (CHD) and subsequent myocardial infarction.

Two basic approaches can be taken to lower cholesterol. One is a public health strategy aimed at bringing down the cholesterol level of the population through awareness and education. The second way is patient-based, emphasizing identification of individuals at high risk for CHD who will benefit from dietary intervention and drug therapy.

The patient-based approach was the subject of a January 1988 report by the National Cholesterol Education Program Expert Panel. This report envisions a pivotal role for the laboratory-performing accurate and precise testing on a large scale, and not only collating the data but also interpreting results and educating the medical staff. Following are the panel's recommendations on cholesterol and triglyceride testing, lab methods, interpretation, and reporting.

*Cholesterol. The Expert Panel recommends fasting or non-fasting cholesterol testing at least once every five years for all persons 20 years and older. It has established three main risk groups based on total cholesterol values: Individuals with total blood cholesterol of less than 200 mg/dl are at a desirable level; those at 200 to 239 mg/di are borderline high; and those at 240 mg/dl or greater are high. These classifications are quite different from previous recommendations based on age- and sex-related reference intervals.

Anyone with a total cholesterol of 200 mg/di or greater should have the value confirmed by repeat testing, according to the Expert Panel. The average of the two tests is used as a guide for further decision making. Recommended follow-up and assessment of additional risk are based on the algorithm shown in Figure 1. The risk factors that are assessed include:

1. Sex-males are at higher risk.

2. Family history of premature coronary heart disease-myocardial infarct in a parent or sibling younger than 55 years of age.

3. Cigarette smoking-more than 10 cigarettes per day.

4. Hypertension.

5. Low HDL cholesterol-less than 35 mg/dl.

6. Diabetes mellitus.

7. History of cerebrovascular accident or peripheral vascular disease.

8. Obesity-more than 30 per cent overweight.

Being a male automatically imparts a two- to fourfold greater risk of coronary heart disease. The other risk factors, apart from those dealing with medical history, can be modified in patients to decrease the rate of CHD.

Patients who have a total cholesterol of 240 mg/dl and above, or 200 to 239 mg/dl with two or more risk factors, are candidates for further lipoprotein analysis: quantitations of high-density lipoprotein cholesterol (HDL), the fraction involved in transport and metabolism of cholesterol; very low-density lipoprotein cholesterol (VLDL), which is predominantly the triglyceride-bound fraction; and low-density lipoprotein cholesterol (LDL), the fraction involved in the development of coronary atheroscierosis.

The lipoprotein analysis is important. In some individuals, especially women, the major portion of the total blood cholesterol may be HDL rather than LDL. Although there is some debate as to whether HDL is an independent risk factor, data seem to indicate that the higher the HDL, the lower the risk of coronary heart disease. Conversely, reduced HDL levels (below 35 mg/dl) impart an increased risk. Factors contributing to low HDL include heavy smoking, which has a worse effect when combined with a heavy intake of coffee; obesity; lack of physical exercise; and the use of anabolic steroids or progestational agents.

Dietary treatment, with or without drug therapy, "is recommended to an extent determined by the results of the lipoprotein analysis for HDL, LDL, and VLDL. The treatment algorithm is shown in Figure II.

A great deal of evidence links LDL cholesterol to coronary heart disease. When present in excess, LDL is the major form of cholesterol that is taken up by arterial subendothelial macrophages. This leads to cholesterol plaque formation and vascular obstruction. The presence of the risk factors previously described accelerates the process. For this reason, an LDL level of 130 to 159 mg/dl plus two or more risk factors, or an LDL of 160 mg/dl or higher, signal the need for a more aggressive approach in terms of lower LDL goals, more frequent monitoring, closer attention to diet, and drug therapy where appropriate.

According to United States population studies and studies of individuals who have emigrated from countries where the average cholesterol level is extremely low, the typical American diet appears to be a major contributing factor to hypercholesterolemia. One can reasonably expect a 10 to 15 per cent decrease in blood cholesterol when following the American Heart Association dietary recommendations endorsed by the expert panel (Figure III).

Inherited disorders of cholesterol metabolism also contribute to the more severely elevated cases of hypercholesterolemia (Figure IV). Although diet may not always be the primary etiology of elevated cholesterol, it should always be the treatment of choice. Drug therapy should be initiated only when patients fail to respond to dietary manipulation.

Dietary goals are established based on the LDL values, as shown in the algorithm in Figure V. The use of ratios such as LDL/HDL or total cholesterol/ HDL to evaluate the risk of coronary heart disease is no longer recommended.

As one can see from the discussion thus far, there is no universal table for calculating the risk of coronary heart disease, and it is difficult to say whether one risk factor is more important than another. It does seem clear that a history of coronary heart disease in a patient or a history of premature CHD in a parent or sibling is extremely important and may suggest treatment to further lower total cholesterol even when the initial value is below 200 mg/dl.

* Triglycerides. Although not listed as an independent risk factor for CHD, triglycerides are also addressed by the Expert Panel. Secondary causes of elevated triglycerides should always be considered, including obesity, excessive alcohol use, diabetes mellitus, hypothyroidism, chronic renal disease, and medications. Modification of these factors is the primary mode of therapy.

Triglyceride levels between 250 and 500 mg/dl are considered borderline high and usually represent an increase in VLDL cholesterol. Once secondary causes are excluded, familial hypeririglyceridemia (FHTG) should be considered. This appears to be a mild defect in the lipolysis of triglyceride-rich lipoproteins combined with larger triglyceride-enriched VLDL particles. Dietary intervention and increased exercise are the recommended treatment. Drug therapy generally is not appropriate.

Levels above 500 mg/dl warrant the label "definite hypertriglyceridemia" and carry a risk of xanthomata and pancreatitis. Patients in this category have primary or secondary disorders of triglyceride metabolism; chylomicronemia is often present. Very high levels (greater than 1,000 mg/dl) may be associated with the congenital absence of lipoprotein lipase or apolipoprotein C-2, the latter disorder usually manifesting itself in childhood. In these cases, control of triglyceride levels by dietary and drug therapy is mandated.

Occasionally, increased triglycerides will alternate with increased LDL cholesterol. This pattern has been termed familial combined hyperlipidemia (FCHL). Patients with FCHL may show elevations of both LDL and VLDL on some occasions, and an elevation of just one of the lipoprotein fractions on other occasions. Thus two repeat measurements are advised prior to initiating therapy. The presence of varying phenotypes in first-degree relatives also points to FCHL.

*Laboratory methods. Although total cholesterol can be measured in outpatients on a fasting or non-fasting basis, in-hospital serum lipid values should not be used to evaluate cardiovascular risk. Evidence suggests that prolonged total fasting induces ketosis and a rise in serum cholesterol, while a partial fast, in which no fat is ingested and carbohydrates are the only source of calories, induces a fall in cholesterol. A 12hour fast should precede outpatient testing if triglycerides and the lipoprotein fractions are also to be measured.

Some of the more common methods for assessing lipoproteins are ultracentrifugation, electrophoresis, precipitation, enzyme chemistry, visual observation, and immunochemistry.

Chylomicrons are generally assessed by looking for a white, creamy layer on top of the serum after storing the specimen overnight in a refrigerator. Since the chylomicrons tend to redissolve when the specimen reaches room temperature, or upon any shaking of the tube, it is necessary to examine the specimen immediately after removing it from the refrigerator. Chylomicrons can also be observed after electrophoresis, as they remain at the origin of application and can be identified with a lipid stain, such as Oil Red 0.

High-density lipoproteins can be analyzed by ultracentrifugation, electrophoresis, or precipitation. Ultracentrifugation is a research method occasionally used to corroborate an electrophoretic or precipitation result or to diagnose a relatively rare Type III hyperlipoproteinemia.

Electrophoresis separates HDL, VLDL, and LDL. The electrophoretic plate can subsequently be stained for lipids with Oil Red 0 or for cholesterol by using a coupled enzymatic assay. Both staining methods are followed by a densitometric scanning to yield the final quantitative result. In addition, HDL can be quantified by precipitating the VLDL and LDL with phosphotungstic acid or heparin and manganese chloride, followed by enzymatic assay for the HDL cholesterol that remains in the supernatant.

LDL cholesterol can be analyzed by ultracentrifugation or electrophoresis in a manner similar to HDL. However, for practical purposes, it is often calculated from the total cholesterol result and the HDL cholesterol result by the following formula:

LDL C - total C

(HDL C + triglycerides/5)

Note that dividing the triglycerides by 5 provides an estimate of VLDL cholesterol. When the triglyceride value exceeds 500 mg/dl, the estimate is no longer valid, and this formula should not be used. VLDL can also be analyzed by ultracentrifugation and electrophoresis.

Apolipoproteins have begun to receive considerable attention, and the A- 1 and B apolipoproteins can be analyzed by a variety of immunochemical procedures. The ratios of LDL cholesterol/apolipoprotein B and apolipoprotein B/ apolipoprotein A-1 appear to be related to the risk of cardiovascular disease. It is too early, however, to say whether these ratios are independent risk factors and yield additional risk information.

Because of the differences encountered with varying methodologies, all cholesterol assays should be standardized to a reference material. We use a trilevel standard available from the College of American Pathologists. Its cholesterol values have been determined through an isotope dilution mass spectrometry method developed by the National Institute of Standards and Technology (former ly the National Bureau of Standards). To further verify our procedures, we split specimens with the Lipid Research Clinic at Columbia University in New York.

*Interpretation and reporting. A clear concise format is necessary for the extensive information now available via lipoprotein analysis. An example of our reporting format is shown in Figure VI. The test menu lists the lipoprotein analysis a "Lipid Profile Consultation." By requiring our hospital's physicians to order a consultation, we fulfill one of the Medicare requirements for part B billing.

The reference intervals for cholesterol, triglycerides, and LDL cholesterol are based on National Cholesterol Education Program Expert Panel guidelines for treatment. The panel's arbitrary cutoffs are not the traditional reference ranges based on the 95th percentile but rather the critical values that signal physician intervention. For HDL and VLDL cholesterol, which do not have such critical values, the more traditional 95th percentile of the population is used."'

Although much more information can be included on the report form, we have chosen to concentrate on three important areas:

Additional factors influencing triglyceride measurements. Serum triglycerides are more susceptible to daily dietary variation than cholesterol. A 12-hour fast is necessary prior to testing. Triglycerides are also affected by obesity, alcohol intake, and a variety of medications. Although triglycerides do not appear to be an independent risk factor for CHD, except in certain specified conditions," elevations may be associated with pancreatitis and skin tophi. In addition, a change in the serum triglyceride level will affect the LDL cholesterol estimate calculated from the formula described above.

Additional risk factors for CHD. These other risk factors are noted because of their pivotal role in determining the need for further testing and in establishing goals. With the presence of two or more risk factors, lower dietary goals are set for LDL cholesterol.

Additional comments, interprefive reporting. Several cutoff levels for various lipoproteins and lipoprotein combinations have been computer-programmed so that comments can be added where appropriate. These cutoffs are based on recommendations of the National Cholesterol Education Program Expert Panel. All comments stress the importance of clinical examination, evaluation of secondary causes and familial history, and the influence of age, sex, and other risk factors. Repeat measurements are a must prior to initiating treatment. In most cases, a trial of diet alone should be undertaken initially. It can be augmented later by drug therapy if necessary.

Recommendations for the testing and treatment of children have not yet been formulated. We use a reference interval based on the 95th percentile."' Ideal weight, a reasonable exercise program, and a sound diet are advised for children above the reference interval. Drug therapy is not recommended for children at this time.

How much interpretive reporting to do is a matter for the laboratory director to decide. Definitive diagnoses cannot be made from laboratory values alone, but guidance and recommendations for a course of medical action can be provided.

As the field gets more complex with the advent of routine apolipoprotein analysis, the laboratory is in a position to enlighten practitioners who may be confused and dismayed by the wealth of available information.

COPYRIGHT 1989 Nelson Publishing
COPYRIGHT 2004 Gale Group