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Diagnosis of Hyperlipoproteinemias

IN THE LAST FEW YEARS, knowledge of the hyperlipidemias (more precisely, hyperlipoproteinemias) has progressed to the point that we can define certain disorders precisely and manage some of them with impressive results. Others can be categorized but it is not clear that they represent discrete inborn errors of metabolism in the genetic sense. Division of hyperlipoproteinemias into five types has greatly facilitated diagnosis and management. As Levy points out in his succinct review in this issue of CALIFORNIA MEDICINE, electrophoresis of lipoproteins on paper or other supporting media is being widely adopted as a routine method for this "phenotyping." The procedure is rapid and simple to perform and provides a graphic record. Unfortunately, the patterns often are not clear-cut and experience has shown that they are frequently misinterpreted. When five observers were asked to type 20 patterns from I to V, in only a third was there complete agreement and in only about twothirds did a given observer make the correct diagnosis as determined by more extensive studies.' Last year, a detailed family study was reported2 purporting to demonstrate dominant inheritance of hyperlipoproteinemia in a family in which some members had type III and others type IV (type III is usually thought to be a recessive trait). T'he published electrophoretic patterns and other information in this paper have led me to conclude that the author was dealing exclusively with familial type IV disease, a judgment corroborated by others. Such confusion may be somewhat less with agarose or cellulose acetate electrophoresis than with paper, since the pre-beta and beta bands are more clearly separated. However, we have found that particles in the lower size range for chylomicrons are more likely to migrate in the electric field on agarose, a feature of this medium that can lead to classification of type V subjects as type IV. Our experience with these and other procedures has led us to propose an alternate approach to classification which we believe will be less confusing to the practicing physician.3 It is based on measurement of cholesterol and triglycerides in fasting serum together with visual assessment of the apof the serum after it has been allowed to stand in the cold for one to two days. This method provides both phenotyping and quantitative data
pearance

essential in evaluation of therapeutic measures. Measurement of cholesterol is readily available to all physicians. Triglyceride measurements are performed in relatively few laboratories. Recently, a new and extremely simple method for estimating triglycerides has become available.4 It is based on quantitative assessment of the lightscattering property of the triglyceride-rich, pre-beta lipoproteins in a nephelometer. * Built into the method is detection of chylomicrons (present in type I and type V hyperlipoproteinemias) from measurement of light scattering before and after passing diluted serum through an appropriate microporous filter. With this method, as with electrophoresis, type III remains the chief source of confusion. Type III disease is one of the rarest of the hyperlipoproteinemias (probably second only to type I) and in the great majority of patients can be diagnosed or at least strongly suspected by the presence of planar and tuberous xanthomas. Unequivocal diagnosis of type III hyperlipoproteinemia requires ultracentrifugation of the serum at its own density, followed by demonstration that the lipoproteins floating to the top of the ultracentrifuge tube have beta mobility or abnormal chemical composition. This procedure is currently performed only in a few research laboratories. Dr. Levy clearly points out that effective treatment is available for two of the three hyperlipoproteinemias that constitute specific disease entities. These are the rare type I and type III disorders, otherwise termed familial hyperchylomicronemia and xanthoma tuberosum, respectively. Treatment of type II disease (familial hyper-betalipoproteinemia), a much more common disorder, is acknowledged to be difficult, but the group at the National Heart Institute and others have reported good results with large amounts of the bile acid sequestering agent, cholestyramine. This drug, used to relieve itching in obstructive jaundice, has not been released for other purposes. It seems likely that it or similar agents will become available in the near future. Our own experience leads us to conclude that patients with endogenous hypertriglyceridemias (types III, IV and V) generally respond well to caloric restriction, which is usually indicated for accompanying obesity. Restriction of simple sugars may also be useful. In addition, limitation of caffeine and nicotine may be helpful, since these drugs increase mobilization of fat from adipose tissue to
*An instrument designed for this purpose is manufactured by Partide Data, Inc., Elmhurst, Ill.

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liver and thus increase formation of endogenous plasma triglycerides. We have also found that excessive intake of ethanol often contributes to severity of hyperlipemia, particularly in type V disease; frequently these patients revert to type IV (disappearance of chylomicrons) when they abstain from ethanol. Type IV disease is by far the most common type of endogenous hypertriglyceridemia. It probably represents a complicated interplay of genetic and environmental factors analogous to the maturityonset form of diabetes mellitus. The analogy with diabetes extends to the most important environmental "inducer" (overnutrition) and the most important therapeutic measure (caloric restriction). Use of drugs should be limited to those patients who respond inadequately or who are unwilling to adhere to a therapeutic diet. Again, as in diabetes, therapy must be life-long. Experience with one drug, p-chlorophenoxyisobutyrate (AtromidS), has been rather extensive, but certain untoward effects have recently been reported and the mechanism by which it lowers triglycerides is unknown. According to Strisower, in type IV disease this drug often fails to reduce cholesterol levels as triglyceride levels fall.5 This has also 'been our experience in patients who have responded partially to diet and it indicates that levels of cholesterol-rich beta lipoproteins are increasing as the levels of triglyceride-rich pre-beta lipoproteins are reduced. Whether such a result is desirable or undesirable is unknown. Accumulated evidence from several types of investigation provides a rational and reasonably persuasive argument for treatment of hyperlipoproteinemias as a method to delay or prevent complications of atherosclerosis. It has been pointed out earlier in these columns that we reduce levels of blood glucose in insulin-independent diabetics for reasons that are, if anything, less clear.6 Our diagnostic tools for the hyperlipoproteinemias have improved remarkably and it is irrational to ignore these methods which provide the basis of treatment specific for definable disorders of lipid transport. RICHARD J. HAVEL, M.D.
Unsity of Caifornia San Francisco Medi Center

Med., 109:173, Aug. 1968.

4. Stone, M. C, et al: A new technique for the investiuation of the low-density lipoproteins in health and disease, ain. Chum. Acta, 14:812, 1966. 5. Strisower, E. H., et al: Treatment of hyperlipidemias, Am. J. Med., 45:488, 1968. 6. Prevention of ischemic vascular disease (an Editorial): Calif.

Health Teams
HEALTH TEAMS are not new in medicine, but they are increasingly important. The need for health teams results primarily from the accomplishments of scientific technology. No single physician nor anyone else can perform every service that even a single patient may require, let alone single handed render all the health care a community, the environment, or the species itself needs or should have. Health professionals can substantially extend the reach of scarce, highly trained personnel, such as physicians and dentists for example, and make them far more productive. Furthermore, only combinations of health professionals can deal effectively with many of the technologically complex problems. Health teams are the order of today and surely they will be of tomorrow. They will not only increase the amount and quality of health care rendered but they will also increase the cost. If health teams are likely to play so important a role in health care delivery, they should be carefully examined and studied. It is necessary to begin with some sort of definition. The Second Planning and Goals Conference, sponsored by the Committee on Continuing Education of the California Medical Association, proposed a definition which says, "The health team may be defined as a number of persons in the allied health professions and other health personnel associated together to accomplish a common objective in health care by cooperation and coordinated action." This definition has been approved by the Scientific Board and accepted by the Council of the California Medical Association as a basis for further study. An example of a health team in practice is reported by Martin in this issue of CALIFORNIA MEDICINE. A non-physician team, under physician supervision and direction, performed pelvic examinations and cytologic screening tests in a population group which almost certainly would not otherwise have received this particular health service. Six of 1,400 women screened were found to have cancer which would otherwise not have been detected. This is an example of but one kind of more or

Mediine and Deprtment of Research Instisste Cadiovascuar

1. Pries, C., et al: Primary hyperlipoproteinemia: the dinicochemi. cal dassification of the most common types, Clin. Chim. Acta, 19:181,

1968.

2. Matthews, R. J.: Type m and IV familial hyperlipoproreinemia. Am. J. Med., 44:188, 1968. 3. Havel, R. J.: Pathogenesis, differentiation and ent of hyperlipemia, In Advances in Intermal Medicine, (G. H. Stllerman, ed),Year Book Medical Publishers, Inc., in press.

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JUNE 1969 * 110 * 6

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