The
Lipid Hypothesis
Genetic Basis Charles J.
Glueck, MD, Peter O. Kwiterovich, Jr,
MD
present evidence that hyperlipidemia, particularly genetically determined elevations of plasma cholesterol or triglyceride levels, facilitates the development of atherosclerosis. (Arch Surg 113:35-41, 1978) \s=b\ We
recently emphasized by population and family studies that suggest that increased amounts of plasma high-density lipoproteins (HDL) have a "protective," rather than a detrimental, effect on the development of atherosclero¬ sis.1"-12
is that plasma involved in the of atherosclerosis. The accumula¬ tion of lipid in the arterial wall involves at least three processes: the transfer of plasma lipids or lipoproteins from blood to the artery, the binding and sequestration of lipids in the arterial wall, and the metabolism and removal of lipids or lipoproteins from the artery.1 The purpose of this report is to review the evidence that hyperlipidemia, particularly genetically determined elevations of plasma cholesterol or triglycéride levels, facilitates the develop¬ ment of atherosclerosis. The data that suggest that the lowering of plasma lipid levels in hyperlipidemia alters the atherosclerotic process will be covered elsewhere. We shall not discuss in detail other genetically determined factors that, alone or in concert with hyperlipidemia, may partici¬ pate in the atherosclerosis process. Examples of these include hypertension, genetic disorders other than familial hyperlipidemia, abnormalities in the structure and func¬ tion of platelets, endothelial cells, and arterial smoothmuscle cells.2-3 The molecular basis or mechanism(s) whereby hyperlipi¬ demia affects the rate of atherosclerosis is unknown. Yet, a considerable amount of epidemiological data exist that is associated with strongly suggest that hyperlipidemia " premature atherosclerosis.1 The lipid hypothesis is further strengthened by family studies where members affected with genetically determined hyperlipidemia have a marked predilection for early atherosclerosis.71' These inherited disorders provide useful models to investigate the role of plasma lipoproteins, as well as lipids, in athero¬ sclerosis and premature vascular disease. The importance of the lipoproteins in the lipid hypothesis has been also
supposition lipid hypothesis The lipids, particularly cholesterol, complex pathophysiology of the
are
Accepted for publication July 1,
1977. From the General Clinical Research Center and Lipid Research Clinic, University of Cincinnati College of Medicine (Dr Glueck) and the Lipid Research Clinic, Departments of Pediatrics and Medicine, Johns Hopkins University School of Medicine, Baltimore (Dr Kwiterovich). Reprint requests to General Clinical Research Center, Cincinnati General Hospital, 234 Goodman St, Cincinnati, OH 45267 (Dr Glueck).
PLASMA LIPIDS AND LIPOPROTEINS The theoretical aspects of normal lipid and lipoprotein metabolism and their practical implications for atheroscle¬ rosis are briefly discussed. A recent complete review is available for more detail.13 There are several classes of lipids in plasma. We will be primarily concerned here with plasma cholesterol and triglycérides. These lipids are carried through the plasma in lipoproteins (Table 1). Chylomicrons are the richest in triglycéride and have the least amount of protein. They have the highest flotation rate and remain at the origin of a paper electrophoretic strip. Chylomicrons are synthesized in the intestinal mucosal cells and transport neutral fat of dietary origin. Very-low-density lipoproteins (VLDL) are also rich in triglycéride and have prebeta electrophoretic mobility. Very-low-density lipoproteins are primarily synthesized in the liver and transport neutral fat that has been made from fatty acid and carbohydrate precursors. The first step in the removal of chylomicrons and VLDL from the circulation is performed by the action of the enzyme(s) lipoprotein lipase at the surface of capillary endothelial cells. Triglycérides are hydrolyzed and the free fatty acids enter the cells, where they are reesterified into triglycér¬ ide. One of the C polypeptides, apoC-II, is a cofactor for this reaction. During the course of lipolysis, the C polypep¬ tides (Table 1) are transferred from VLDL to HDL. The catabolism of VLDL also involves the enzyme lecithin-cholesterol acyl transferase. Lecithin-cholesterol acyl transferase circulates in the plasma as a complex with HDL, where it catalyzes the transfer of a molecule of fatty acid from lecithin to the 3-hydroxyl group of cholesterol to form cholesteryl esters and lysolecithin. The major apoprotein of high-density lipoproteins, apoA-1, is a cofactor for this reaction (Table 1). Lecithin-cholesterol acyl trans¬ ferase does not act directly on VLDL, but apparently participates in its catabolism by using lecithin and choles¬ terol that have been received from VLDL, thereby stimu¬ lating further removal of these lipids from VLDL. The lipoprotein products of lipolysis, chylomicron and VLDL
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/14/2015
Table 1.—Classification and
Migration on paper electrophoresis Density ranges (gm/ml), ultracentrifuge Average composition
Chylomicrons Origin 1,000 mg/100
Appearance
Lipoproteins ml
Chylomicrons greatly
increased
Thick, creamy layer
of
Plasma!
over
clear
infranant
_
high; TG normal
Ma
C
lib
C
high; TG high
III
C
high; TG high
LDL increased LDL & VLDL increased VLDL with prebeta mobility & abnormal
Clear
VLDL increased, LDL normal Chylomicrons & VLDL increased
Slightly cloudy
Sightly cloudy to turbid Cloudy to milky (rarely, cream layer)
_C/TG ratio_ to IV
V
C normal or high; TG high C high; TG > 1,000 mg/100 ml
turbid
Thick, creamy layer
over
infranant
*C indicates cholesterol; TG, triglycérides; LDL, low-density (beta) lipoproteins; and VLDL, very-low-density (prebeta) lipoproteins. tCriteria of abnormality are those presented for group A In Table 1. ^Assumes that plasma was obtained from fasting patient and stored at 4 C overnight.
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/14/2015
turbid
individuals.7-22 Subjects homozygous for familial hypercho¬ lesterolemia are quite rare (one per million), usually have a total plasma cholesterol level above 600 mg/100 ml and LDL levels above 500 mg/100 ml; despite the most vigorous treatment, tendon and tuberous xanthomas develop in childhood, and they usually have lethal atherosclerosis well before age 25.16-25 The close association of monogenic familial hypercholesterolemia with premature ischémie heart disease has been well documented. The risks of myocardial infarction morbidity for the male hétérozygote by age 50 are at least 50%, and the risk of death at least 25% or higher.26-27 The risk of a first myocardial infarction for female hétérozygotes is 12% to 35% by age 50.26-27 By age 60, the risk of a morbid or lethal coronary event is 65% or greater in affected males and 36% in women, as compared to 16% in normal men and 14% in normal women.9'26-27 Patients with familial hypercholesterolemia have signifi¬ cantly lower HDL cholesterol levels, which are present from birth or early childhood.161928 These low HDL levels may possibly contribute to the precocious atherosclerosis of familial hypercholesterolemia subjects. An important advance in the investigation of the genetic mechanisms of familial hypercholesterolemia came with a series of elegant experiments by Brown and Goldstein,29 who used fibroblasts grown in tissue culture from homozy¬ gotes and their obligate heterozygous parents. These workers demonstrated a lack of functional LDL receptors (receptor-negative) or an alteration in the LDL receptor (receptor-defective) on the cell membrane of cultured fibroblasts from patients with familial hypercholesterol¬ emia.30 Inability to bind LDL was associated with several abnormalities of lipid and lipoprotein metabolism that included a lack of feedback inhibition of the rate-limiting enzyme of cholesterol biosynthesis, hydroxymethylglutaryl-coenzyme A reducíase, decreased conversion of choles¬ terol to cholesteryl ester, and deficient proteolysis of LDL.29 Several intriguing questions remain. What is the molec¬ ular basis for the inability of the surface of these cells to bind LDL? What is the relationship of the absence of this receptor to the pathogenesis of atherosclerosis in familial hypercholesterolemia and to the in vivo catabolism of LDL? Of interest in this regard are the recent observations that glycosphingolipids and phospholipids are stored in familial hypercholesterolemia fibroblasts, in the presence of lipo¬ proteins in the tissue culture media.31 The increases in these lipids revert to normal levels in the absence of lipoproteins, suggesting that LDL, through its receptor, may be involved in the regulation of a variety of lipids. Further, since these apparent abnormalities in glycosphingolipid and phospholipid regulation occur in the presence of lipoproteins, they may exist in vivo and contribute, at least in part, to the accelerated atherosclerosis in familial hyper¬ cholesterolemia. In addition to the alterations of the glycosphingolipids on the cell surface, distinct alterations have also been observed in the cell surface glycoproteins in this disorder.32 The relationship between these cell surface alterations, cellular lipid and lipoprotein metabolism, and atherosclerosis remains to be elucidated.
Primary Type
IV
Hyperlipoproteinemia
The primary type IV lipoprotein pattern is characterized by increased triglycéride and VLDL cholesterol levels in plasma obtained from fasting subjects. Low-density lipo¬ protein cholesterol is normal; the total plasma cholesterol
level may be somewhat elevated if the VLDL concentra¬ tions are sufficiently high. Type IV hyperlipoproteinemia is undoubtedly the most genetically heterogeneous of all the familial hyperlipidemias.23 It is part of the phenotypic presentation of at least four "monogenic" disorders. The distribution of lipoprotein patterns for familial hyperlipi¬ demia is as follows:
Monogenic
Model
Familial hypercholesterolemia Familial hypertriglyceridemia Familial combined hyperlipidemia Broad B disease (type III
hyperlipoproteinemia) Exogenous and endogenous hypertriglyceridemia 'Occasionally type V.
Lipoprotein Pattern, Type Ha, lib IV
Ha, lib, IV* HI, IV
V, IV
specific phenotype has emerged, kindreds having "familial hypertriglyceridemia" IV (familial type hyperlipoproteinemia) after family screening has uncovered a cluster of relatives whose hyper¬ lipidemia is confined to type IV lipoprotein patterns. A "monogenic" model is suggested by the presence of bimodality in the triglycéride distribution in first-degree rela¬ tives and when segregation ratio analyses in first-degree Because no classified
are
as
relatives demonstrate, on the average, a ratio of one affected to one unaffected patient.7 The elucidation of specific biochemical defects will probably uncover genetic heterogeneity even in these families with familial type IV
hyperlipoproteinemia. Age-dependent penetrance
was
involved in most of the kindreds in whom familial type IV hyperlipoproteinemia appeared to be segregating as a "dominant" trait. Approximately one out of five chil¬ dren born to an affected parent have hypertriglyceridemia (in comparison with the 50% expected Mendelian
trait).716-33 Although familial type IV hyperlipoproteinemia is thought to be associated with an increased risk of prema¬ ture cardiovascular morbidity and mortality,7-16 Brunzell et al34 recently found no excessive prevalence of early vascular disease in kindreds with familial type IV hyperlip¬ oproteinemia, compared to control populations. There is also some current controversy concerning hypertriglycer¬ 27
idemia
as a
risk factor for ischémie heart disease in the
general population. Rhoads and co-workers" found no relation between type IV hyperlipoproteinemia and preva¬ lence of coronary heart disease in a Hawaii Japanese population. Carlson and Bottiger,7' however, found that hypercholesterolemia or hypertriglyceridemia alone were risk factors and that a patient with an elevation in both lipid levels was at greater risk than a subject with hyper¬ cholesterolemia or hypertriglyceridemia alone.
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/14/2015
Relationship to Other Types of Hyperlipoproteinemia Part of the apparent discrepancy between the results of
the above studies on hypertriglyceridemia and risk for cardiovascular disease may reside in the chemical, genetic, and clinical heterogeneity of type IV hyperlipoproteine¬ mia.23 It is not known whether the type IV subjects in kindreds with various kinds of familial hyperlipidemia differ from those found in kindreds where type IV breeds true. Nor is it known whether the biochemical defects in these patients are confined to a metabolic disorder that affects the plasma lipids and lipoproteins, or whether there are other associated phenotypic effects that include various cell types and their organdíes. The possible biochemical disorders in type IV hyperlipoproteinemia are many but may be lumped together as increased rate of VLDL synthesis, decreased rate of removal of VLDL from the circulation, and combination of increased synthesis and decreased removal. The genetic defects may involve a structural or qualitative change in the protein components of the lipoproteins or of the cells involved in lipid and lipoprotein metabolism. Finally, a mutation may occur that affects the regulation of the quantity of a particular
protein.
FAMILIAL COMBINED HYPERLIPIDEMIA
The entity "familial combined hyperlipidemia" was first described as a monogenic model of familial hyperlipidemia by Goldstein and co-workers.7 The great predilection to atherosclerotic cardiovascular disease in these patients has been well documented and familial combined hyperlipi¬ demia may be the most common form of familial hyperlip¬ idemia in survivors of myocardial infarction.723 The genetic forms of hyperlipidemia in these survivors are as follows:
Monogenic familial hypercholesterolemia Familial hypertriglyceridemia Familial combined hyperlipidemia Type III hyperlipoproteinemia Polygenic and sporadic Unclassified *Data is
myocardial
Frequency, %* 10 14 30 2.4 31 12.6
compiled from the 157 hyperlipidemic survivors of infarction studied by Goldstein and co-workers.7
None of the Fredrickson lipoprotein "types" is strictly comparable with familial combined hyperlipidemia. In the hypothesis put forward by Goldstein et al,7 familial combined hyperlipidemia exhibits three lipoprotein pat¬ terns (Ha, lib, and IV) as the varied expression of mutant gene(s) at a single locus. The diagnosis of familial combined hyperlipidemia is, therefore, based on the find¬ ings observed in the pedigree and cannot be securely made on an individual's lipoprotein pattern. The difficulties over the interpretation of these genetic analyses have been recently discussed in some detail923; they include the confounding effects of the correlation of cholesterol with triglycérides and the possible bias towards bimodality in the distribution of the relatives, when families are grouped
to the hyperlipidemia in the propositus and at least one affected first degree relative. Nonetheless, it is not unreasonable to consider familial combined hyperlipi¬ demia as a probable major gene disorder, with the caveat that competing genetic hypotheses have not been rigor¬ ously excluded and that familial combined hyperlipidemia is presumably a heterogeneous group of disorders. Indeed, a number of kindreds have been described in the literature in whom various combinations of lipid and lipoprotein elevations were present.23 The difficulty inherent in studying these complex families has been recently demonstrated by Namboodiri et al,35 who reexamined 33 families in which the probands had a type lib lipoprotein pattern (Table 3); these kindreds had originally been described as having familial combined hyperlipidemia.36 They concluded, from a bivariate analyses of the cholesterol and triglycéride levels, that "the initial analyses performed here give no indication that the genetic mechanism involved is any different in these families than for familial hypercholesterolemia."35 They also performed a similar analysis of the lipid data from the families with familial combined hyperlipidemia reported by Goldstein et al.7 The results of their analysis suggested that the primary metabolic defect in familial combined hyperlipidemia may reside in the metabolism of triglyc¬ érides. This interpretation of their own analyses of the Seattle data is in agreement with the hypothesis put forward by Goldstein et al.7
according
TYPE III HYPERLIPOPROTEINEMIA
Type III hyperlipoproteinemia, or the "floating beta" disorder, may be defined by the presence of a plasma VLDL that has an abnormal chemical composition and migrates on electrophoresis with the ß- rather than prebeta lipoproteins (/3-VLDL).16 Both hypercholesterol¬ emia and hypertriglyceridemia are generally present (Table 3). A rather large proportion of the patients have tuberous and tendon xanthomas, in particular, unusual deposits in the creases of hands (xanthoma striata palmaris).16-37 These patients are also susceptible to premature coronary and peripheral vascular disease.1"37 The preva¬ lence of familial type III hyperlipoproteinemia in unselected populations is not accurately known, but it appears to be considerably rarer than the other forms of monogenic hyperlipidemia.717-23-37
The familial nature of type III hyperlipoproteinemia perhaps first suggested by Gofman and co-workers,38 who described two affected sisters with "xanthoma tuberosum" and an abnormal lipoprotein pattern in the analytical ultracentrifuge. Subsequently, Fredrickson and Levy16 described a relatively large number of patients with type III hyperlipoproteinemia; this same group has very recently reported that the "qualitative" marker, floating ßlipoproteins, was present in other lipoproteinemias and, furthermore, was not even consistently detectable in the plasma of some patients previously classified as type III.18 Thus, the presence of /S-VLDL can no longer be considered a "qualitative" and distinctive genetic trait, and the recur¬ ring theme of genetic heterogeneity is again evident. was
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/14/2015
If one examines some of the available pedigrees16-37-39 with the above information in mind and further supposes a monogenic mechanism, the observations are not incompat¬ ible with a mutation at a single locus with variable expression of the gene (that is, type IV hyperlipoproteine¬ mia). Possible biochemical defects include increased production of VLDL or /3-VLDL, a block in the normal metabolism of VLDL to LDL (deficient lipase), or a faulty uptake of "remnants," ie, lipoproteins intermediate between VLDL and LDL.23 /3-very-low-density lipoproteins contain unusually large amounts of an arginine-rich apolipoprotein that is ordinarily only a minor protein compo¬ nent of normal VLDL (Table l).13-40 The relationship of the accumulation of this polypeptide to the pathogenesis of type III hyperlipoproteinemia is not presently known. Elucidation of the basic biochemical defect(s) in type III hyperlipoproteinemia may have important implications for our understanding of the interrelationships of lipids, lipo¬ proteins, and atherosclerosis. In type III hyperlipoprotein¬ emia, the atherosclerosis appears different than the garden variety and is characterized by the presence of lipid-laden foam cells." The pathophysiology of vascular disease in this disorder has clinical relevance, since the amelioration of hyperlipidemia with diet and drugs is followed by objective improvement in the peripheral circu¬ lation.12
Type V Hyperlipoproteinemia Primary type V hyperlipoproteinemia is a diverse group
of disorders in which exogenous hypertriglyceridemia (chylomicrons being present in the fasting state) is
accompanied by endogenous hypertriglyceridemia (in¬ very-low-density [prebeta] lipoproteins).16 The hypertriglyceridemia is often severe (greater than 2,000 mg/100 ml), and in adults is frequently accompanied by pancreatitis, abdominal pain, hepatosplenomegaly, erup¬ tive xanthomas, abnormal glucose tolerance, and hyperuricemia.16-43 The first-degree relatives of propositi with type V hyperlipoproteinemia may also have a similar lipoprotein pattern, but in many instances they have simple type IV hyperlipoproteinemia.1643 Studies by Fredrickson and Levy16 and Fallat and Glueck" are compatible with the hypothesis that type V hyperlipoproteinemia is the extreme expression of a heterozygous dominant trait that in its milder form may present as type IV hyperlipoprote¬ inemia. The expression of hypertriglyceridemia in these families is delayed and only about 20% of children of affected parents have hypertriglyceridemia.16-43 Most of these children have type IV hyperlipoproteinemia,16-43 although the expression of type V hyperlipoproteinemia in préadolescent children has recently been described.41 In some kindreds, the first-degree relatives of a type V patient appear to have familial combined hyperlipidemia. Thus, the type V lipoprotein patterns often have a familial basis, but the degree of genetic heterogeneity and the creased
nature of the metabolic
defect(s) remains unknown.23 with type V hyperlipoproteinemia may have normal or low levels of lipoprotein lipase.15 The enzymatic activities of lipoprotein lipase and histaminase (enzymes
Subjects
by heparin sodium) may provide clues to underlying biochemical and genetic heterogeneity.44 Of further interest in this regard is the recent description of the apparent absence of the cofactor for lipoprotein lipase, apolipoprotein C-II, in a patient with type V hyperlipopro¬ teinemia.16 A better understanding of the pathophysiology of type V hyperlipoproteinemia may shed further light on the lipid hypothesis and the relative atherogenicity of lipoproteins. Type V subjects appear to have a lower prevalence of premature vascular disease than do patients with the other types of "monogenic" hyperlipidemia. released
Indeed, several studies have found low levels of LDL, one of the most atherogenic of the lipoproteins, in type V subjects.44 The hypertriglyceridemia due to chylomicronemia may not be as atherogenic as that due to increased VLDL; this appears to be the case at least with the rare type I hyperlipoproteinemia, and may also be true in type V
hyperlipoproteinemia.
GENETIC MODELS OF HYPERLIPOPROTEINEMIAS AND HYPOPROTEINEMIAS Type I Hyperlipoproteinemia
Type I hyperlipoproteinemia is a rare disorder (about 40 in the world literature) characterized by excessive hyperchylomicronemia and hypertriglyceridemia; the hy¬ percholesterolemia is mild compared to the hypertriglycer¬ idemia, and the triglycéride/cholesterol ratio is usually greater than ten.16 Type I hyperlipoproteinemia is believed cases
double dose of a mutant alíele with Affected patients have a severe deficiency in the enzyme lipoprotein lipase.16 In the patients studied to date, the hyperlipidemia does not appear to be associated with premature atherosclerosis.1" to be the result of
recessive
a
phenotype.16
Familial
Hyperalphalipoproteinemia
Familial hyperalphalipoproteinemia is a recently charac¬ terized trait that aggregates in families.12 It is character¬ ized by plasma concentrations of HDL cholesterol that are in the upper 5% to 10% of the distribution curve for HDL. It is accompanied by mild hypercholesterolemia (usually levels found in group B, but occasionally those also found in group A) (Table 1). The levels of LDL, VLDL, and triglyc¬ érides are normal.12 The genetics of familial hyperalpha¬ lipoproteinemia are far from understood and shared envi¬ ronmental influences may contribute significantly to the familial aggregation.12 "Affected" subjects have, in a fashion similar to those from the general population (with elevated HDL levels), some apparent "protection" from the development of ischémie heart disease.12 Longevity is significantly prolonged in hyperalphalipoproteinemic kindreds, as compared to US population statistics.12 Familial
Hypobetalipoproteinemia
Familial hypobetalipoproteinemia is characterized by low levels of total and LDL cholesterol, with both being below the fifth percentile. Like hyperalphalipoprotein¬ emia, this disorder appears to confer a decreased risk for cardiovascular disease and an increased life span.12 In some families, it may appear to segregate as a dominant disor-
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/14/2015
der, but the interpretation of the genetic data is again subject to the nonspecific nature of "low LDL cholesterol." In any case, hypobetalipoproteinemia, accompanied by hypocholesterolemia, appears to be the antithesis of hyperbetalipoproteinemia (Table 3) in its atherogenicity. This again argues for the atherogenic properties of LDL. COMMENT In the context of atherosclerosis as a multifaceted, complex disease process, the genetic basis of the lipid hypothesis has been reviewed. The heterogeneity underly¬ ing the various genetic models for hyperlipidemia is appar¬ ent. In view of the probable relative atherogenicity of the lipoprotein classes and the probable beneficial effect from an increase in one of them, it may be more appropriate to specifically focus on the genetic basis of the lipoprotein, rather than the lipid hypothesis per se. This study was supported in part by the General Clinical Research Center grant RP 00068-14, American Heart Association, Established Investigatorship 1971 through 1976 (Dr Glueck). Dr Glueck is a recipient of National Heart, Lung, and Blood Institute contract 72 2914 L; Dr Kwiterovich is a recipient of National Heart and Lung Institute grant 17898-01.
References 1. Zilversmit DB: Mechanisms of cholesterol accumulation in the arterial wall. Am J Cardiol 35:559-566, 1975. 2. Murphy EA: Genetic factors in coronary heart disease. Sandorama 2:4\x=req-\
6, 1975.
3. Ross R, Glomset J: The pathogenesis of atherosclerosis. N Engl J Med 295:369-377, 1976. 4. Kannel WB, Castelli WP, Gordon T, et al: Serum cholesterol, lipoproteins and the risk of coronary heart disease. Ann Intern Med 74:1-12,
1971. 5. Carlson LA, Bottiger LE: Ischemic heart disease in relation to fasting values of plasma triglycerides and cholesterol. Lancet 1:865-868, 1972. 6. Goldstein JL, Hazzard WR, Schrott JG, et al: Hyperlipidemia in coronary heart disease: I. Lipid levels in 500 survivors of myocardial infarction. J Clin Invest 52:1533-1577, 1973. 7. Goldstein JL, Schrott HG, Hazzard WR, et al: Hyperlipidemia in coronary heart disease: II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest 52:1544-1568, 1973. 8. Glueck CJ, Fallat RW: The heritable hyperlipoproteinemias and atherosclerosis, in Kritchevsky D, Paoletti R, Holmes WC (eds): Lipids, Lipoproteins and Drugs. New York, Plenum Press Inc, 1974, pp 305-316. 9. Slack J: Genetic aspects of lipoprotein abnormalities. Postgrad Med J 8(suppl 51):27-32, 1975. 10. Miller GJ, Miller NE: Plasma high density lipoprotein concentration and development of ischemic heart disease. Lancet 1:16-19, 1975. 11. Rhoads GG, Gulbrandsen CL, Kagan A: Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men. New Engl J Med 294:293-298, 1976. 12. Glueck CJ, Gartside P, Fallat RW, et al: Longevity syndromes: Familial hypobeta and familial hyperalphalipoproteinemia. J Lab Clin Med 88:941-957, 1976. 13. Morrisett JP, Jackson RL, Gotto AM Jr: Lipoproteins: Structure and function. Ann Rev Biochem 44:183-207, 1975. 14. Carew TE, Koschinsky T, Hayes SB, et al: A mechanism by which high density lipoproteins may slow the atherogenic process. Lancet 1:1315-1317, 1976. 15. Sing CF, Chamberlain MA, Black WD, et al: Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan: I. Analysis of the frequency distribution for evidence of a genetic polymorphism. Am J Human Genet 27:333-347, 1975. 16. Fredrickson DS, Levy RI: Familial hyperlipoproteinemias, in Stanbury JB, Wyngaarden JB, Fredrickson DS (eds): The Metabolic Basis of Inherited Disease, ed 3. New York, McGraw-Hill Book Co Inc, 1972, pp 545\x=req-\ 614. 17. Hazzard WR, Goldstein JL, Schrott HG, et al: Hyperlipidemia in coronary heart disease: III. Evaluation of lipoprotein phenotypes of 156 genetically defined survivors of myocardial infarction. J Clin Invest 52:1569-1577, 1973. 18. Fredrickson DS, Morganroth J, Levy RI: Type III hyperlipoprotein-
emia: An
157,1975.
analysis of two contemporary definitions. Ann Intern Med 82:150\x=req-\
19. Kwiterovich PO, Fredrickson DS, Levy RI: Familial hypercholesterolemia: One form of familial type II hyperlipoproteinemia. J Clin Invest 53:1237-1249, 1974. 20. Elston RC, Namboodiri KK, Glueck CJ, et al: Study of the genetic transmission of hypercholesterolemia and hypertriglyceridemia in a 195 member kindred. Ann Human Genet 39:67-87, 1975. 21. Heiberg A: Inheritance of xanthomatosis and hyper-\g=b\-lipoproteinaemia: A study in 7 large kindreds. Clin Genet 9:92-111, 1976. 22. Tsang RC, Fallat RW, Glueck CJ: Cholesterol at birth and age 1: Comparison of normal and hypercholesterolemic neonates. Pediatrics
53:458-470, 1974. 23. Murphy EA, Kwiterovich PO: Genetics of hyperlipoproteinemias, in Rifkind B, Levy RI (eds): Diagnosis and Treatment of Hyperlipidemia. New York, Grune & Stratton Inc, 1977. 24. Langer T, Strober W, Levy RI: The metabolism of low density lipoprotein in familial type II hyperlipoproteinemia. J Clin Invest 51:1528\x=req-\ 1536,1972. 25. Khachadurian AK, Uthman SM: Experiences with the homozygous cases of familial hypercholesterolemia: A report of 52 patients. Nutr Metabol 15:132-140, 1973. 26. Stone NJ, Levy RI, Fredrickson DS, et al: Coronary artery disease in 116 kindreds with familial type II hyperlipoproteinemia. Circulation 49:476\x=req-\ 488, 1974.
27. Slack J: Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states. Lancet 2:1380, 1969. 28. Kwiterovich PO, Levy RI, Fredrickson DS: Neonatal diagnosis of familial type II hyperlipoproteinemia. Lancet 1:118-122, 1973. 29. Brown MS, Goldstein JL: Receptor-mediated control of cholesterol metabolism. Science 191:150-154, 1976. 30. Goldstein JL, Dana SE, Brunsched GY, et al: Genetic heterogeneity in familial hypercholesterolemia: Evidence for two different mutations affecting functions of low density lipoprotein receptors. Proc Natl Acad Sci USA 72:1092-1096, 1975. 31. Chatterjee S, Sekerke CS, Kwiterovich PO: Alterations in the cell surface glycosphingolipids and other lipid classes of fibroblasts in familial hypercholesterolemia. Proc Natl Acad Sci USA 71:4339-4343, 1976. 32. Chatterjee S, Kwiterovich PO: Alterations in the cell surface glycosphingolipids and glycoproteins of fibroblasts in familial hypercholesterolemia. Circulation 54(suppl 2):55, 1976. 33. Glueck CJ, Tsang R, Fallat R, et al: Familial hypertriglyceridemia: Studies in 130 children and 45 siblings of 36 index cases. Metabolism 22:1287\x=req-\ 1309, 1973. 34. Brunzell JD, Schrott HG, Motulsky AG, et al: Myocardial infarction in familial forms of hypertriglyceridemia. Metabolism 25:313, 1976. 35. Namboodiri KK, Elston RC, Glueck CJ, et al: Bivariate analyses of cholesterol and triglyceride levels in families in which probands have the type lib lipoprotein phenotype. Am J Human Genet 27:454-471, 1975. 36. Glueck CJ, Fallat CR, Buncher R, et al: Familial combined hyperlipoproteinemia: Studies in 91 adults and 95 children from 33 kindreds Metabolism 22:1403-1428, 1973. 37. Morganroth J, Levy RI, Fredrickson DS: Biochemical, clinical and genetic features of type III hyperlipoproteinemia. Ann Intern Med 82:158\x=req-\ 174, 1975. 38. Gofman JN, deLalla O, Glazier F, et al: The serum lipoprotein transport system in health, metabolic disorders, atherosclerosis and coronary artery disease. Plasma 2:413-484, 1954. 39. Hazzard WR, O'Donnel TE, Lee YL: Broad-beta disease (type III hyperlipoproteinemia) in a large kindred. Ann Intern Med 82:141-149, 1975. 40. Havel RJ, Fase JP: Primary dysbetalipoproteinemia: Predominance of a specific population species in triglyceride-rich lipoproteins. Proc Natl Acad Sci USA 70:2015-2019, 1975. 41. Roberts W, Levy RI, Fredrickson DS: Hyperlipoproteinemia: A review of the five types with the first report of necropsy findings in type 3. Arch Pathol 90:46-56, 1970. 42. Zelis R, Mason DT, Braunwald E, et al: Effects of hyperlipoproteinemia and their treatment on the peripheral circulation. J Clin Invest 49:1007-1015, 1970. 43. Fallat RW, Glueck CJ: Familial and acquired type V hyperlipoproteinemia. Atherosclerosis 23:41-62, 1976. 44. Kwiterovich PO, Farah JR, Brown VB, et al: Biochemical, clinical and familial presentation of type V hyperlipoproteinemia in childhood. Pediatrics, to be published. 45. Gretin H, DeGrella R, Klose G, et al: Measurement of two plasma triglyceride lipases by an immunochemical method: Studies in patients with hypertriglyceridemia. J Lipid Res 17:203:210, 1976. 46. Breckenridge WC, Little JA, Steiner G, et al: Hyperlipoproteinemia associated with an absence of C-II apoprotein in plasma lipoproteins. Circulation 54(suppl 2):25, 1976.
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/14/2015
Lipid Hypothesis
Genetic Basis Charles J.
Glueck, MD, Peter O. Kwiterovich, Jr,
MD
present evidence that hyperlipidemia, particularly genetically determined elevations of plasma cholesterol or triglyceride levels, facilitates the development of atherosclerosis. (Arch Surg 113:35-41, 1978) \s=b\ We
recently emphasized by population and family studies that suggest that increased amounts of plasma high-density lipoproteins (HDL) have a "protective," rather than a detrimental, effect on the development of atherosclero¬ sis.1"-12
is that plasma involved in the of atherosclerosis. The accumula¬ tion of lipid in the arterial wall involves at least three processes: the transfer of plasma lipids or lipoproteins from blood to the artery, the binding and sequestration of lipids in the arterial wall, and the metabolism and removal of lipids or lipoproteins from the artery.1 The purpose of this report is to review the evidence that hyperlipidemia, particularly genetically determined elevations of plasma cholesterol or triglycéride levels, facilitates the develop¬ ment of atherosclerosis. The data that suggest that the lowering of plasma lipid levels in hyperlipidemia alters the atherosclerotic process will be covered elsewhere. We shall not discuss in detail other genetically determined factors that, alone or in concert with hyperlipidemia, may partici¬ pate in the atherosclerosis process. Examples of these include hypertension, genetic disorders other than familial hyperlipidemia, abnormalities in the structure and func¬ tion of platelets, endothelial cells, and arterial smoothmuscle cells.2-3 The molecular basis or mechanism(s) whereby hyperlipi¬ demia affects the rate of atherosclerosis is unknown. Yet, a considerable amount of epidemiological data exist that is associated with strongly suggest that hyperlipidemia " premature atherosclerosis.1 The lipid hypothesis is further strengthened by family studies where members affected with genetically determined hyperlipidemia have a marked predilection for early atherosclerosis.71' These inherited disorders provide useful models to investigate the role of plasma lipoproteins, as well as lipids, in athero¬ sclerosis and premature vascular disease. The importance of the lipoproteins in the lipid hypothesis has been also
supposition lipid hypothesis The lipids, particularly cholesterol, complex pathophysiology of the
are
Accepted for publication July 1,
1977. From the General Clinical Research Center and Lipid Research Clinic, University of Cincinnati College of Medicine (Dr Glueck) and the Lipid Research Clinic, Departments of Pediatrics and Medicine, Johns Hopkins University School of Medicine, Baltimore (Dr Kwiterovich). Reprint requests to General Clinical Research Center, Cincinnati General Hospital, 234 Goodman St, Cincinnati, OH 45267 (Dr Glueck).
PLASMA LIPIDS AND LIPOPROTEINS The theoretical aspects of normal lipid and lipoprotein metabolism and their practical implications for atheroscle¬ rosis are briefly discussed. A recent complete review is available for more detail.13 There are several classes of lipids in plasma. We will be primarily concerned here with plasma cholesterol and triglycérides. These lipids are carried through the plasma in lipoproteins (Table 1). Chylomicrons are the richest in triglycéride and have the least amount of protein. They have the highest flotation rate and remain at the origin of a paper electrophoretic strip. Chylomicrons are synthesized in the intestinal mucosal cells and transport neutral fat of dietary origin. Very-low-density lipoproteins (VLDL) are also rich in triglycéride and have prebeta electrophoretic mobility. Very-low-density lipoproteins are primarily synthesized in the liver and transport neutral fat that has been made from fatty acid and carbohydrate precursors. The first step in the removal of chylomicrons and VLDL from the circulation is performed by the action of the enzyme(s) lipoprotein lipase at the surface of capillary endothelial cells. Triglycérides are hydrolyzed and the free fatty acids enter the cells, where they are reesterified into triglycér¬ ide. One of the C polypeptides, apoC-II, is a cofactor for this reaction. During the course of lipolysis, the C polypep¬ tides (Table 1) are transferred from VLDL to HDL. The catabolism of VLDL also involves the enzyme lecithin-cholesterol acyl transferase. Lecithin-cholesterol acyl transferase circulates in the plasma as a complex with HDL, where it catalyzes the transfer of a molecule of fatty acid from lecithin to the 3-hydroxyl group of cholesterol to form cholesteryl esters and lysolecithin. The major apoprotein of high-density lipoproteins, apoA-1, is a cofactor for this reaction (Table 1). Lecithin-cholesterol acyl trans¬ ferase does not act directly on VLDL, but apparently participates in its catabolism by using lecithin and choles¬ terol that have been received from VLDL, thereby stimu¬ lating further removal of these lipids from VLDL. The lipoprotein products of lipolysis, chylomicron and VLDL
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/14/2015
Table 1.—Classification and
Migration on paper electrophoresis Density ranges (gm/ml), ultracentrifuge Average composition
Chylomicrons Origin 1,000 mg/100
Appearance
Lipoproteins ml
Chylomicrons greatly
increased
Thick, creamy layer
of
Plasma!
over
clear
infranant
_
high; TG normal
Ma
C
lib
C
high; TG high
III
C
high; TG high
LDL increased LDL & VLDL increased VLDL with prebeta mobility & abnormal
Clear
VLDL increased, LDL normal Chylomicrons & VLDL increased
Slightly cloudy
Sightly cloudy to turbid Cloudy to milky (rarely, cream layer)
_C/TG ratio_ to IV
V
C normal or high; TG high C high; TG > 1,000 mg/100 ml
turbid
Thick, creamy layer
over
infranant
*C indicates cholesterol; TG, triglycérides; LDL, low-density (beta) lipoproteins; and VLDL, very-low-density (prebeta) lipoproteins. tCriteria of abnormality are those presented for group A In Table 1. ^Assumes that plasma was obtained from fasting patient and stored at 4 C overnight.
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/14/2015
turbid
individuals.7-22 Subjects homozygous for familial hypercho¬ lesterolemia are quite rare (one per million), usually have a total plasma cholesterol level above 600 mg/100 ml and LDL levels above 500 mg/100 ml; despite the most vigorous treatment, tendon and tuberous xanthomas develop in childhood, and they usually have lethal atherosclerosis well before age 25.16-25 The close association of monogenic familial hypercholesterolemia with premature ischémie heart disease has been well documented. The risks of myocardial infarction morbidity for the male hétérozygote by age 50 are at least 50%, and the risk of death at least 25% or higher.26-27 The risk of a first myocardial infarction for female hétérozygotes is 12% to 35% by age 50.26-27 By age 60, the risk of a morbid or lethal coronary event is 65% or greater in affected males and 36% in women, as compared to 16% in normal men and 14% in normal women.9'26-27 Patients with familial hypercholesterolemia have signifi¬ cantly lower HDL cholesterol levels, which are present from birth or early childhood.161928 These low HDL levels may possibly contribute to the precocious atherosclerosis of familial hypercholesterolemia subjects. An important advance in the investigation of the genetic mechanisms of familial hypercholesterolemia came with a series of elegant experiments by Brown and Goldstein,29 who used fibroblasts grown in tissue culture from homozy¬ gotes and their obligate heterozygous parents. These workers demonstrated a lack of functional LDL receptors (receptor-negative) or an alteration in the LDL receptor (receptor-defective) on the cell membrane of cultured fibroblasts from patients with familial hypercholesterol¬ emia.30 Inability to bind LDL was associated with several abnormalities of lipid and lipoprotein metabolism that included a lack of feedback inhibition of the rate-limiting enzyme of cholesterol biosynthesis, hydroxymethylglutaryl-coenzyme A reducíase, decreased conversion of choles¬ terol to cholesteryl ester, and deficient proteolysis of LDL.29 Several intriguing questions remain. What is the molec¬ ular basis for the inability of the surface of these cells to bind LDL? What is the relationship of the absence of this receptor to the pathogenesis of atherosclerosis in familial hypercholesterolemia and to the in vivo catabolism of LDL? Of interest in this regard are the recent observations that glycosphingolipids and phospholipids are stored in familial hypercholesterolemia fibroblasts, in the presence of lipo¬ proteins in the tissue culture media.31 The increases in these lipids revert to normal levels in the absence of lipoproteins, suggesting that LDL, through its receptor, may be involved in the regulation of a variety of lipids. Further, since these apparent abnormalities in glycosphingolipid and phospholipid regulation occur in the presence of lipoproteins, they may exist in vivo and contribute, at least in part, to the accelerated atherosclerosis in familial hyper¬ cholesterolemia. In addition to the alterations of the glycosphingolipids on the cell surface, distinct alterations have also been observed in the cell surface glycoproteins in this disorder.32 The relationship between these cell surface alterations, cellular lipid and lipoprotein metabolism, and atherosclerosis remains to be elucidated.
Primary Type
IV
Hyperlipoproteinemia
The primary type IV lipoprotein pattern is characterized by increased triglycéride and VLDL cholesterol levels in plasma obtained from fasting subjects. Low-density lipo¬ protein cholesterol is normal; the total plasma cholesterol
level may be somewhat elevated if the VLDL concentra¬ tions are sufficiently high. Type IV hyperlipoproteinemia is undoubtedly the most genetically heterogeneous of all the familial hyperlipidemias.23 It is part of the phenotypic presentation of at least four "monogenic" disorders. The distribution of lipoprotein patterns for familial hyperlipi¬ demia is as follows:
Monogenic
Model
Familial hypercholesterolemia Familial hypertriglyceridemia Familial combined hyperlipidemia Broad B disease (type III
hyperlipoproteinemia) Exogenous and endogenous hypertriglyceridemia 'Occasionally type V.
Lipoprotein Pattern, Type Ha, lib IV
Ha, lib, IV* HI, IV
V, IV
specific phenotype has emerged, kindreds having "familial hypertriglyceridemia" IV (familial type hyperlipoproteinemia) after family screening has uncovered a cluster of relatives whose hyper¬ lipidemia is confined to type IV lipoprotein patterns. A "monogenic" model is suggested by the presence of bimodality in the triglycéride distribution in first-degree rela¬ tives and when segregation ratio analyses in first-degree Because no classified
are
as
relatives demonstrate, on the average, a ratio of one affected to one unaffected patient.7 The elucidation of specific biochemical defects will probably uncover genetic heterogeneity even in these families with familial type IV
hyperlipoproteinemia. Age-dependent penetrance
was
involved in most of the kindreds in whom familial type IV hyperlipoproteinemia appeared to be segregating as a "dominant" trait. Approximately one out of five chil¬ dren born to an affected parent have hypertriglyceridemia (in comparison with the 50% expected Mendelian
trait).716-33 Although familial type IV hyperlipoproteinemia is thought to be associated with an increased risk of prema¬ ture cardiovascular morbidity and mortality,7-16 Brunzell et al34 recently found no excessive prevalence of early vascular disease in kindreds with familial type IV hyperlip¬ oproteinemia, compared to control populations. There is also some current controversy concerning hypertriglycer¬ 27
idemia
as a
risk factor for ischémie heart disease in the
general population. Rhoads and co-workers" found no relation between type IV hyperlipoproteinemia and preva¬ lence of coronary heart disease in a Hawaii Japanese population. Carlson and Bottiger,7' however, found that hypercholesterolemia or hypertriglyceridemia alone were risk factors and that a patient with an elevation in both lipid levels was at greater risk than a subject with hyper¬ cholesterolemia or hypertriglyceridemia alone.
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/14/2015
Relationship to Other Types of Hyperlipoproteinemia Part of the apparent discrepancy between the results of
the above studies on hypertriglyceridemia and risk for cardiovascular disease may reside in the chemical, genetic, and clinical heterogeneity of type IV hyperlipoproteine¬ mia.23 It is not known whether the type IV subjects in kindreds with various kinds of familial hyperlipidemia differ from those found in kindreds where type IV breeds true. Nor is it known whether the biochemical defects in these patients are confined to a metabolic disorder that affects the plasma lipids and lipoproteins, or whether there are other associated phenotypic effects that include various cell types and their organdíes. The possible biochemical disorders in type IV hyperlipoproteinemia are many but may be lumped together as increased rate of VLDL synthesis, decreased rate of removal of VLDL from the circulation, and combination of increased synthesis and decreased removal. The genetic defects may involve a structural or qualitative change in the protein components of the lipoproteins or of the cells involved in lipid and lipoprotein metabolism. Finally, a mutation may occur that affects the regulation of the quantity of a particular
protein.
FAMILIAL COMBINED HYPERLIPIDEMIA
The entity "familial combined hyperlipidemia" was first described as a monogenic model of familial hyperlipidemia by Goldstein and co-workers.7 The great predilection to atherosclerotic cardiovascular disease in these patients has been well documented and familial combined hyperlipi¬ demia may be the most common form of familial hyperlip¬ idemia in survivors of myocardial infarction.723 The genetic forms of hyperlipidemia in these survivors are as follows:
Monogenic familial hypercholesterolemia Familial hypertriglyceridemia Familial combined hyperlipidemia Type III hyperlipoproteinemia Polygenic and sporadic Unclassified *Data is
myocardial
Frequency, %* 10 14 30 2.4 31 12.6
compiled from the 157 hyperlipidemic survivors of infarction studied by Goldstein and co-workers.7
None of the Fredrickson lipoprotein "types" is strictly comparable with familial combined hyperlipidemia. In the hypothesis put forward by Goldstein et al,7 familial combined hyperlipidemia exhibits three lipoprotein pat¬ terns (Ha, lib, and IV) as the varied expression of mutant gene(s) at a single locus. The diagnosis of familial combined hyperlipidemia is, therefore, based on the find¬ ings observed in the pedigree and cannot be securely made on an individual's lipoprotein pattern. The difficulties over the interpretation of these genetic analyses have been recently discussed in some detail923; they include the confounding effects of the correlation of cholesterol with triglycérides and the possible bias towards bimodality in the distribution of the relatives, when families are grouped
to the hyperlipidemia in the propositus and at least one affected first degree relative. Nonetheless, it is not unreasonable to consider familial combined hyperlipi¬ demia as a probable major gene disorder, with the caveat that competing genetic hypotheses have not been rigor¬ ously excluded and that familial combined hyperlipidemia is presumably a heterogeneous group of disorders. Indeed, a number of kindreds have been described in the literature in whom various combinations of lipid and lipoprotein elevations were present.23 The difficulty inherent in studying these complex families has been recently demonstrated by Namboodiri et al,35 who reexamined 33 families in which the probands had a type lib lipoprotein pattern (Table 3); these kindreds had originally been described as having familial combined hyperlipidemia.36 They concluded, from a bivariate analyses of the cholesterol and triglycéride levels, that "the initial analyses performed here give no indication that the genetic mechanism involved is any different in these families than for familial hypercholesterolemia."35 They also performed a similar analysis of the lipid data from the families with familial combined hyperlipidemia reported by Goldstein et al.7 The results of their analysis suggested that the primary metabolic defect in familial combined hyperlipidemia may reside in the metabolism of triglyc¬ érides. This interpretation of their own analyses of the Seattle data is in agreement with the hypothesis put forward by Goldstein et al.7
according
TYPE III HYPERLIPOPROTEINEMIA
Type III hyperlipoproteinemia, or the "floating beta" disorder, may be defined by the presence of a plasma VLDL that has an abnormal chemical composition and migrates on electrophoresis with the ß- rather than prebeta lipoproteins (/3-VLDL).16 Both hypercholesterol¬ emia and hypertriglyceridemia are generally present (Table 3). A rather large proportion of the patients have tuberous and tendon xanthomas, in particular, unusual deposits in the creases of hands (xanthoma striata palmaris).16-37 These patients are also susceptible to premature coronary and peripheral vascular disease.1"37 The preva¬ lence of familial type III hyperlipoproteinemia in unselected populations is not accurately known, but it appears to be considerably rarer than the other forms of monogenic hyperlipidemia.717-23-37
The familial nature of type III hyperlipoproteinemia perhaps first suggested by Gofman and co-workers,38 who described two affected sisters with "xanthoma tuberosum" and an abnormal lipoprotein pattern in the analytical ultracentrifuge. Subsequently, Fredrickson and Levy16 described a relatively large number of patients with type III hyperlipoproteinemia; this same group has very recently reported that the "qualitative" marker, floating ßlipoproteins, was present in other lipoproteinemias and, furthermore, was not even consistently detectable in the plasma of some patients previously classified as type III.18 Thus, the presence of /S-VLDL can no longer be considered a "qualitative" and distinctive genetic trait, and the recur¬ ring theme of genetic heterogeneity is again evident. was
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/14/2015
If one examines some of the available pedigrees16-37-39 with the above information in mind and further supposes a monogenic mechanism, the observations are not incompat¬ ible with a mutation at a single locus with variable expression of the gene (that is, type IV hyperlipoproteine¬ mia). Possible biochemical defects include increased production of VLDL or /3-VLDL, a block in the normal metabolism of VLDL to LDL (deficient lipase), or a faulty uptake of "remnants," ie, lipoproteins intermediate between VLDL and LDL.23 /3-very-low-density lipoproteins contain unusually large amounts of an arginine-rich apolipoprotein that is ordinarily only a minor protein compo¬ nent of normal VLDL (Table l).13-40 The relationship of the accumulation of this polypeptide to the pathogenesis of type III hyperlipoproteinemia is not presently known. Elucidation of the basic biochemical defect(s) in type III hyperlipoproteinemia may have important implications for our understanding of the interrelationships of lipids, lipo¬ proteins, and atherosclerosis. In type III hyperlipoprotein¬ emia, the atherosclerosis appears different than the garden variety and is characterized by the presence of lipid-laden foam cells." The pathophysiology of vascular disease in this disorder has clinical relevance, since the amelioration of hyperlipidemia with diet and drugs is followed by objective improvement in the peripheral circu¬ lation.12
Type V Hyperlipoproteinemia Primary type V hyperlipoproteinemia is a diverse group
of disorders in which exogenous hypertriglyceridemia (chylomicrons being present in the fasting state) is
accompanied by endogenous hypertriglyceridemia (in¬ very-low-density [prebeta] lipoproteins).16 The hypertriglyceridemia is often severe (greater than 2,000 mg/100 ml), and in adults is frequently accompanied by pancreatitis, abdominal pain, hepatosplenomegaly, erup¬ tive xanthomas, abnormal glucose tolerance, and hyperuricemia.16-43 The first-degree relatives of propositi with type V hyperlipoproteinemia may also have a similar lipoprotein pattern, but in many instances they have simple type IV hyperlipoproteinemia.1643 Studies by Fredrickson and Levy16 and Fallat and Glueck" are compatible with the hypothesis that type V hyperlipoproteinemia is the extreme expression of a heterozygous dominant trait that in its milder form may present as type IV hyperlipoprote¬ inemia. The expression of hypertriglyceridemia in these families is delayed and only about 20% of children of affected parents have hypertriglyceridemia.16-43 Most of these children have type IV hyperlipoproteinemia,16-43 although the expression of type V hyperlipoproteinemia in préadolescent children has recently been described.41 In some kindreds, the first-degree relatives of a type V patient appear to have familial combined hyperlipidemia. Thus, the type V lipoprotein patterns often have a familial basis, but the degree of genetic heterogeneity and the creased
nature of the metabolic
defect(s) remains unknown.23 with type V hyperlipoproteinemia may have normal or low levels of lipoprotein lipase.15 The enzymatic activities of lipoprotein lipase and histaminase (enzymes
Subjects
by heparin sodium) may provide clues to underlying biochemical and genetic heterogeneity.44 Of further interest in this regard is the recent description of the apparent absence of the cofactor for lipoprotein lipase, apolipoprotein C-II, in a patient with type V hyperlipopro¬ teinemia.16 A better understanding of the pathophysiology of type V hyperlipoproteinemia may shed further light on the lipid hypothesis and the relative atherogenicity of lipoproteins. Type V subjects appear to have a lower prevalence of premature vascular disease than do patients with the other types of "monogenic" hyperlipidemia. released
Indeed, several studies have found low levels of LDL, one of the most atherogenic of the lipoproteins, in type V subjects.44 The hypertriglyceridemia due to chylomicronemia may not be as atherogenic as that due to increased VLDL; this appears to be the case at least with the rare type I hyperlipoproteinemia, and may also be true in type V
hyperlipoproteinemia.
GENETIC MODELS OF HYPERLIPOPROTEINEMIAS AND HYPOPROTEINEMIAS Type I Hyperlipoproteinemia
Type I hyperlipoproteinemia is a rare disorder (about 40 in the world literature) characterized by excessive hyperchylomicronemia and hypertriglyceridemia; the hy¬ percholesterolemia is mild compared to the hypertriglycer¬ idemia, and the triglycéride/cholesterol ratio is usually greater than ten.16 Type I hyperlipoproteinemia is believed cases
double dose of a mutant alíele with Affected patients have a severe deficiency in the enzyme lipoprotein lipase.16 In the patients studied to date, the hyperlipidemia does not appear to be associated with premature atherosclerosis.1" to be the result of
recessive
a
phenotype.16
Familial
Hyperalphalipoproteinemia
Familial hyperalphalipoproteinemia is a recently charac¬ terized trait that aggregates in families.12 It is character¬ ized by plasma concentrations of HDL cholesterol that are in the upper 5% to 10% of the distribution curve for HDL. It is accompanied by mild hypercholesterolemia (usually levels found in group B, but occasionally those also found in group A) (Table 1). The levels of LDL, VLDL, and triglyc¬ érides are normal.12 The genetics of familial hyperalpha¬ lipoproteinemia are far from understood and shared envi¬ ronmental influences may contribute significantly to the familial aggregation.12 "Affected" subjects have, in a fashion similar to those from the general population (with elevated HDL levels), some apparent "protection" from the development of ischémie heart disease.12 Longevity is significantly prolonged in hyperalphalipoproteinemic kindreds, as compared to US population statistics.12 Familial
Hypobetalipoproteinemia
Familial hypobetalipoproteinemia is characterized by low levels of total and LDL cholesterol, with both being below the fifth percentile. Like hyperalphalipoprotein¬ emia, this disorder appears to confer a decreased risk for cardiovascular disease and an increased life span.12 In some families, it may appear to segregate as a dominant disor-
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/14/2015
der, but the interpretation of the genetic data is again subject to the nonspecific nature of "low LDL cholesterol." In any case, hypobetalipoproteinemia, accompanied by hypocholesterolemia, appears to be the antithesis of hyperbetalipoproteinemia (Table 3) in its atherogenicity. This again argues for the atherogenic properties of LDL. COMMENT In the context of atherosclerosis as a multifaceted, complex disease process, the genetic basis of the lipid hypothesis has been reviewed. The heterogeneity underly¬ ing the various genetic models for hyperlipidemia is appar¬ ent. In view of the probable relative atherogenicity of the lipoprotein classes and the probable beneficial effect from an increase in one of them, it may be more appropriate to specifically focus on the genetic basis of the lipoprotein, rather than the lipid hypothesis per se. This study was supported in part by the General Clinical Research Center grant RP 00068-14, American Heart Association, Established Investigatorship 1971 through 1976 (Dr Glueck). Dr Glueck is a recipient of National Heart, Lung, and Blood Institute contract 72 2914 L; Dr Kwiterovich is a recipient of National Heart and Lung Institute grant 17898-01.
References 1. Zilversmit DB: Mechanisms of cholesterol accumulation in the arterial wall. Am J Cardiol 35:559-566, 1975. 2. Murphy EA: Genetic factors in coronary heart disease. Sandorama 2:4\x=req-\
6, 1975.
3. Ross R, Glomset J: The pathogenesis of atherosclerosis. N Engl J Med 295:369-377, 1976. 4. Kannel WB, Castelli WP, Gordon T, et al: Serum cholesterol, lipoproteins and the risk of coronary heart disease. Ann Intern Med 74:1-12,
1971. 5. Carlson LA, Bottiger LE: Ischemic heart disease in relation to fasting values of plasma triglycerides and cholesterol. Lancet 1:865-868, 1972. 6. Goldstein JL, Hazzard WR, Schrott JG, et al: Hyperlipidemia in coronary heart disease: I. Lipid levels in 500 survivors of myocardial infarction. J Clin Invest 52:1533-1577, 1973. 7. Goldstein JL, Schrott HG, Hazzard WR, et al: Hyperlipidemia in coronary heart disease: II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest 52:1544-1568, 1973. 8. Glueck CJ, Fallat RW: The heritable hyperlipoproteinemias and atherosclerosis, in Kritchevsky D, Paoletti R, Holmes WC (eds): Lipids, Lipoproteins and Drugs. New York, Plenum Press Inc, 1974, pp 305-316. 9. Slack J: Genetic aspects of lipoprotein abnormalities. Postgrad Med J 8(suppl 51):27-32, 1975. 10. Miller GJ, Miller NE: Plasma high density lipoprotein concentration and development of ischemic heart disease. Lancet 1:16-19, 1975. 11. Rhoads GG, Gulbrandsen CL, Kagan A: Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men. New Engl J Med 294:293-298, 1976. 12. Glueck CJ, Gartside P, Fallat RW, et al: Longevity syndromes: Familial hypobeta and familial hyperalphalipoproteinemia. J Lab Clin Med 88:941-957, 1976. 13. Morrisett JP, Jackson RL, Gotto AM Jr: Lipoproteins: Structure and function. Ann Rev Biochem 44:183-207, 1975. 14. Carew TE, Koschinsky T, Hayes SB, et al: A mechanism by which high density lipoproteins may slow the atherogenic process. Lancet 1:1315-1317, 1976. 15. Sing CF, Chamberlain MA, Black WD, et al: Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan: I. Analysis of the frequency distribution for evidence of a genetic polymorphism. Am J Human Genet 27:333-347, 1975. 16. Fredrickson DS, Levy RI: Familial hyperlipoproteinemias, in Stanbury JB, Wyngaarden JB, Fredrickson DS (eds): The Metabolic Basis of Inherited Disease, ed 3. New York, McGraw-Hill Book Co Inc, 1972, pp 545\x=req-\ 614. 17. Hazzard WR, Goldstein JL, Schrott HG, et al: Hyperlipidemia in coronary heart disease: III. Evaluation of lipoprotein phenotypes of 156 genetically defined survivors of myocardial infarction. J Clin Invest 52:1569-1577, 1973. 18. Fredrickson DS, Morganroth J, Levy RI: Type III hyperlipoprotein-
emia: An
157,1975.
analysis of two contemporary definitions. Ann Intern Med 82:150\x=req-\
19. Kwiterovich PO, Fredrickson DS, Levy RI: Familial hypercholesterolemia: One form of familial type II hyperlipoproteinemia. J Clin Invest 53:1237-1249, 1974. 20. Elston RC, Namboodiri KK, Glueck CJ, et al: Study of the genetic transmission of hypercholesterolemia and hypertriglyceridemia in a 195 member kindred. Ann Human Genet 39:67-87, 1975. 21. Heiberg A: Inheritance of xanthomatosis and hyper-\g=b\-lipoproteinaemia: A study in 7 large kindreds. Clin Genet 9:92-111, 1976. 22. Tsang RC, Fallat RW, Glueck CJ: Cholesterol at birth and age 1: Comparison of normal and hypercholesterolemic neonates. Pediatrics
53:458-470, 1974. 23. Murphy EA, Kwiterovich PO: Genetics of hyperlipoproteinemias, in Rifkind B, Levy RI (eds): Diagnosis and Treatment of Hyperlipidemia. New York, Grune & Stratton Inc, 1977. 24. Langer T, Strober W, Levy RI: The metabolism of low density lipoprotein in familial type II hyperlipoproteinemia. J Clin Invest 51:1528\x=req-\ 1536,1972. 25. Khachadurian AK, Uthman SM: Experiences with the homozygous cases of familial hypercholesterolemia: A report of 52 patients. Nutr Metabol 15:132-140, 1973. 26. Stone NJ, Levy RI, Fredrickson DS, et al: Coronary artery disease in 116 kindreds with familial type II hyperlipoproteinemia. Circulation 49:476\x=req-\ 488, 1974.
27. Slack J: Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states. Lancet 2:1380, 1969. 28. Kwiterovich PO, Levy RI, Fredrickson DS: Neonatal diagnosis of familial type II hyperlipoproteinemia. Lancet 1:118-122, 1973. 29. Brown MS, Goldstein JL: Receptor-mediated control of cholesterol metabolism. Science 191:150-154, 1976. 30. Goldstein JL, Dana SE, Brunsched GY, et al: Genetic heterogeneity in familial hypercholesterolemia: Evidence for two different mutations affecting functions of low density lipoprotein receptors. Proc Natl Acad Sci USA 72:1092-1096, 1975. 31. Chatterjee S, Sekerke CS, Kwiterovich PO: Alterations in the cell surface glycosphingolipids and other lipid classes of fibroblasts in familial hypercholesterolemia. Proc Natl Acad Sci USA 71:4339-4343, 1976. 32. Chatterjee S, Kwiterovich PO: Alterations in the cell surface glycosphingolipids and glycoproteins of fibroblasts in familial hypercholesterolemia. Circulation 54(suppl 2):55, 1976. 33. Glueck CJ, Tsang R, Fallat R, et al: Familial hypertriglyceridemia: Studies in 130 children and 45 siblings of 36 index cases. Metabolism 22:1287\x=req-\ 1309, 1973. 34. Brunzell JD, Schrott HG, Motulsky AG, et al: Myocardial infarction in familial forms of hypertriglyceridemia. Metabolism 25:313, 1976. 35. Namboodiri KK, Elston RC, Glueck CJ, et al: Bivariate analyses of cholesterol and triglyceride levels in families in which probands have the type lib lipoprotein phenotype. Am J Human Genet 27:454-471, 1975. 36. Glueck CJ, Fallat CR, Buncher R, et al: Familial combined hyperlipoproteinemia: Studies in 91 adults and 95 children from 33 kindreds Metabolism 22:1403-1428, 1973. 37. Morganroth J, Levy RI, Fredrickson DS: Biochemical, clinical and genetic features of type III hyperlipoproteinemia. Ann Intern Med 82:158\x=req-\ 174, 1975. 38. Gofman JN, deLalla O, Glazier F, et al: The serum lipoprotein transport system in health, metabolic disorders, atherosclerosis and coronary artery disease. Plasma 2:413-484, 1954. 39. Hazzard WR, O'Donnel TE, Lee YL: Broad-beta disease (type III hyperlipoproteinemia) in a large kindred. Ann Intern Med 82:141-149, 1975. 40. Havel RJ, Fase JP: Primary dysbetalipoproteinemia: Predominance of a specific population species in triglyceride-rich lipoproteins. Proc Natl Acad Sci USA 70:2015-2019, 1975. 41. Roberts W, Levy RI, Fredrickson DS: Hyperlipoproteinemia: A review of the five types with the first report of necropsy findings in type 3. Arch Pathol 90:46-56, 1970. 42. Zelis R, Mason DT, Braunwald E, et al: Effects of hyperlipoproteinemia and their treatment on the peripheral circulation. J Clin Invest 49:1007-1015, 1970. 43. Fallat RW, Glueck CJ: Familial and acquired type V hyperlipoproteinemia. Atherosclerosis 23:41-62, 1976. 44. Kwiterovich PO, Farah JR, Brown VB, et al: Biochemical, clinical and familial presentation of type V hyperlipoproteinemia in childhood. Pediatrics, to be published. 45. Gretin H, DeGrella R, Klose G, et al: Measurement of two plasma triglyceride lipases by an immunochemical method: Studies in patients with hypertriglyceridemia. J Lipid Res 17:203:210, 1976. 46. Breckenridge WC, Little JA, Steiner G, et al: Hyperlipoproteinemia associated with an absence of C-II apoprotein in plasma lipoproteins. Circulation 54(suppl 2):25, 1976.
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/14/2015
