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Familial hypercholesterolemia: Diagnosis, metabolic defect and management
Pergamon Presa
Lifn Sciencna, Vol . 21, pp . 1395-1402 Priated in the II .S .A .
MINIREVIEW FAMILIAL HYPERCHOLESTEROLEMIA : Richard L. Jackson,
DIAGNOSIS, METABOLIC DEPECT AND MANAGEMENT
Louis C . Smith, 0 . David Taunton and Antonio M. Gotto, Jr .
Departments of Medicine and Biochemistry, Baylor College of Medicine and The Methodist Hospital, Houston, Texas 77030
INTRODUCTION Coronary artery disease remains the major cause of death in our society . Slightly under one million people die each year in the United States of some form of cardiovascular disease, with atherosclerosis being the underlying eti ology in the great majority of cases . Hypercholesterolemia has long been known to be one of the major risk factors for premature coronary artery disease . In a study (1,2) of 500 survivors of myocardial infarctions in Seattle, it was estimated that approximately 30$ had some type of familial hyperlipidemia . Three monogenic forms of hyperlipidemia were identified, namely familial hypercholesterolemia, usually manifested as a type II hyperlipoproteinemia phenotype (3), familial endogenous hypertriglyceridemia, usually presenting as a type IV hyperlipoproteinemia phenotype and familial combined hyperlipidemia which may have a type IIb, IV or even a IIa pattern. Other groups of individuals had polygenic or sporadic hypercholesterole~ia . In a general population of middle-aged adults with plasma cholesterol values of 265 mg/dl or greater, and with triglyceride values less than 300 mg/dl, perhaps only 5$ or less of these individuals with elevated lipids will have a monogenic form of familial hypercholesterolemia (PH) (2,4-6) . Due to the work of several laboratories and especially to that of Brown and Goldstein (7-10), a great deal of information has evolved over the past three years from studies of patients with FH . Because of its potential rele vance to the understanding of the metabolism of cholesterol and low density lipoproteins (LDL) in man, it is appropriate to review the current state of knowledge concerning the diagnosis, the clinical manifestations, the metabolic defect and the management of this interesting form of dyslipidemia . DIAGNOSIS OF FH Familial hypercholesterolemia is a monogenic autosomal-dominant disorder, which is characterized by hypercholesterolemia due to increased plasma low density lipoproteins (LDL), xanthomatous lesions skin and tendons, and a family history of hypercholesterolemia, xanthomatosis aid premature coronary artery disease (3) . The disorder occurs in approximately 1 in 200 to 1 in 500 in the general population (2-6) . In patients with heterozygous FH, there is approximately a two-fold elevation above normal values of LDL-cholesterol from birth; the plasma cholesterol level usually reaches 300 to 500 mg/dl by adulthood . In the rare subjects who are homozygous for the FH gene, the clinical manifestations are much more severe with total plasma cholesterol from 500 to
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1000 mg/dl . In families at risk, the condition may be recognized at birth by analysis of umbilical cord blood. While the homozygotes for FH can be identified by specific biochemical tests performed on fibroblasts grown in tissue culture, there is no definitive cellular marker for the heterozygous at the present time . An elevation of cholesterol or LDL early in life or even at birth is probably the best diagnostic criterion at the present time . The minimum characteristics for the diagnosis of homozygous FH include plasma cholesterol levels in excess of 500 mg/dl, hypercholesterolemia in both parents or in both family lines if the parents are deceased and the appearance of xanthomas in the first decade of life . Many children with homozygous FH have atherosclerosis and die of coronary vascular disease before the age of 20 . The prognosis for the homozygote to reach adulthood is poor, the main cause of death being coronary artery disease . Atherosclerosis affects the coronary, peripheral and cerebral arteries of the homozygote . It is not uncommon in the homozygote for aortic cholesteryl ester deposits to cause aortic valvular stenosis . Whereas corneal arcus and cutaneous deposits of cholesteryl ester occur frequently by adulthood in heterozygotes, they occur in childhood in homozygotes . Homozygous children have yellowish deposits (planar xanthomas) over They also develop tendinous xanthomas and dethe buttocks, knees and elbows . posits around the eyelids known as xanthelasma, both of which are found frequently in heterozygous adults . These cutaneous findings are helpful but are not absolutely diagnostic of FH ; a family history is required for an unambiguous diagnosis . Most individuals with hypercholesterolemia have a type IIa or IIb pattern by the criteria of the World Health Organization's system of lipoprotein typing (11) . In type IIa, LDL-cholesterol is increased but triglycerides and VLDL are normal . In type IIb, LDL-cholesterol, VLDL and triglycerides are all The FH subjects can usually be distinguished by higher cholesterol increased . values, by the appearance of tendinous xanthomas at an early age and by a family genetic analysis . As reviewed recently by Brown and Goldstein (12), there have been more than 325 families with well-documented FH described to date ; most PH are type IIa. From these analyses, it has been concluded that the disorder is transmitted as an autosomal dominant monogenic trait . There is at least one diverging view, viz ., that of Jensen and Blankenhorn (13) who suggest the trait is polygenic rather than monogenic. DEFECT IN FH The primary defect in both heterozygous and homozygous foams of FH which can account for the elevated levels of cholesterol and LDL has been investi-. Normal LDL gated through studies of LDL structure, synthesis and catabolism . contains approximately 35$ cholesteryl ester, 10$ unesterified cholesterol, 5~ Most studies have shown very triglyceride, 25$ protein and 25$ phospholipid . Mills et al . little difference between the LDL of normal and FH subjects . (14) have studied two patients with homozygous FH and were unable tofind any major differences in carbohydrate, phospholipid and fatty acid content ; the LDL from the FH subject did, however, have a slightly higher proportion of The molecular cholesterol and a corresponding lower amount of triglyceride . weights and diffusion constants of the LDL were within normal ranges . There is no detectable difference in the amino acid compositions of the LDL protein Lee and Breckenridge (18) have (apoB) between normal and FH subjects (15-17) . also examined the carbohydrate composition of glycopeptides derived from apoB for normal and heterozygous FH and have not found any differences . Cholesterol balance studies and measurement of total fecal endogenous steroids have provided no evidence for an increased rate of cholesterol synthesis in FH (19) . There is also no evidence for an increased absorption of dietary cholesterol (20) . Furthermore, Myant et al . (21) have been unable
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to demonstrate any significant difference in the absolute rates of turnover of LDL-cholesteryl esters in normals and FH heterozygotes . There was, however, a diminished fractional rate of turnover of LDL-cholesteryl esters (21) . The homozygous FH patient has a fractional rate of turnover of LDL-cholesteryl esters about one-half that of the heterozygotes and about one-third that of norThe absolute rate of turnover for all subjects was the same . The mals (21) . lower fractional catabolic rate of turnover in the hamozygote is undoubtedly related to the elevated plasma LDL. Since the cholesterol balance studies have failed to explain the hypercholesterolemia in FH, more recent studies have focused on the metabolism of LDL-protein or apoB . Longer et al . (22) first showed that the fractional catabolic rate of plasma LDL-protéinin 10 heterozygous patients was decreased nearly 50 percent compared to normals. Consequently, the half-life of LDLprotein was significantly prolonged (3 .1 days for normals compared to 4 .7 for type II subjects) ; the absolute catabolic rate for apoB was normal in this study (22) . Packard et al . (23) have re-examined the metabolic fate of LDL in the heterozygotes andconfirmed that the fractional catabolic rate is decreased (0 .164 for the FH subjects compared to 0.312 for normals) . Packard et al . (23) also reported that the FH heterozygote has a 37~ increase in apoprotéin synthesis compared to normals . In the study of Longer et al . (22), the subjects were maintained in a metabolic ward and were fed adiet containing <300 mg of cholesterol/day and high in polyunsaturated fat (P/S, 2 .5) . Packard et al . (23) followed their subjects as out-patients with no modification in their life style and usual diet . The increased synthesis of apoB in FH has also been shown in homozygotes . Simons and coworkers (24,25) found that the fractional catabolic rate is significantly prolonged for homozygotes (0 .175/day as compared to 0 .497 for nor mals) and that the synthesis of apoB is considerably increased in the homozygote . In this study, the subjects ate a diet containing approximately 300 mg cholesterol/day and a polyunsaturated/saturated fat ratio of 2 :1 . The origin of the increased plasma apoB in the homozygote is an important question which needs further study. As reviewed by Eisenberg and Levy (26), most of the plasma apoB in man is derived from the catabolism of chylomicrons and very low density lipoproteins (VLDL) . However, in a preliminary communication, Thompson et al . (27) have simultaneously measured the turnover of apoB in VLDL and LDL two homozygous subjects and have shown that the rate of synthesis of apoB exceeded that of the apoB in VLDL . These results were interpreted as evidence that apoB is derived not only from VLDL but may also be secreted directly into the plasma as LDL .
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In summary, there is both a reduced fractional catabolic rate of LDL and an increased rate of LDL synthesis in the subject with homozygous familial hypercholesterolemia . How can both abnormalities be explained by a singlé ge netic defect which can also account for the monogenicity of the inheritance? As a background for discussing the nature of the catabolic defect in FH, a brief review of normal LDL metabolism is appropriate . Much of the information for LDL catabolism stems from the elegant work of Brown and Goldstein . Their studies [for detailed references, see review articles (7-10)] have delineated a receptor-mediated process by which cultured fibroblasts from normal subjects bind and take up LDL through the mechanism of absorptive endocytosis . According to these authors (7-10), the first critical step in LDL catabolism is its binding to a high-affinity specific plasma membrane receptor ; the binding is stoichiometric . Subsequent to binding, LDL is taken up as a receptorbound LDL into the cell by endocytosis, an energy-dependent process . The internalized LDL fuse with lysosomal vesicles and the cholesteryl esters and
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protein are hydrolyzed to free cholesterol and amino acids . As a result of intracellular cholesterol accumulation, three important events occur . First, there is a reduction in new cholesterol synthesis through the suppression of 3hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase activity . Since this enzyme is one of the rate-limiting steps in the cholesterol biosynthetic pathway, .the rate of synthesis of this sterol declines . Secondly, there is activation of acyl-CoA cholesterol acyltransferase ; thus, some of the cholesterol which is taken up is stored as the ester until it can be further utilized . Finally, when sufficient cellular cholesterol has accumulated, the synthesis of the specific LDL receptor is suppressed . Since the accumulation of LDL requires its receptor for high-affinity uptake, there is a block in further cholesterol transport into the call . In addition to the cultured human fibroblast, Ho et al . (28) and Reichl et al . (29) have shown thât the circulating human lymphocyte also has the capacity to produce a high affinity LDL receptor that mediates the cellular uptake and degradation of LDL. Although they have been less well studied, there is evidence that arterial smooth muscle cells (9,30-32) and leukocytes (33-39) may also regulate cellular cholesterol levels through an LDL receptor . All of these studies support the proposal that non-hepatic tissues constitute a major site for LDL degra dation . An important study which lends support to the role of non-hepatic tissues in LDL degradation has been described by Sniderman et al . (36) . They found that the hepatectomized pig has a greater fractional râtéof plasma LDL degradation than does the intact animal (0 .0764 compared to 0.0457 for the same animals before hepatectomy) . If the extrahepatic tissues are responsible for degradation of LDL, how do FH subjects take up and degrade LDL7 Brown and Goldstein (7-10), Khachadurian et al . (37), Fogelman et al . (33,34), Avigan et al . (38) and Breslow et al .(39) have all suggested that there is a metabolicdefect in the FH subject which results in inability of FH cells to suppress HMG-CoA reductase . Studies by Brown and Goldstein (710) have shown that the failure of LDL to suppress HMG-CoA reductase is actually a secondary effect with the primary one being in the binding of the lipoprotein. Brown and Goldstein have defined two types of mutant cells in patients with FH, either receptor-negative or receptor-defective . In the receptor-negative subject, there are no receptors and, consequently, the cells are unable to bind, internalize and degrade LDL normally . Patients with receptor-negative cells have apparently inherited two defective alleles at the receptor locus . In receptor-defective cells, there is binding and uptake of LDL by a specific high affinity receptor but only to about 10$ of normal . Although patients with heterozygous FH have a 50 percent reduction in LDL receptors, the absolute rates of cholesterol production and LDL degradation are normal . Heterozygotes presumably have one normal and one defective allele for binding. Brown and Goldstein (8) have suggested that the absence of receptors or defective receptors in the subject with homozygous FH is associated with three metabolic consequences . These are a high level of plasma cholesterol, primarily as LDL; a three-fold reduction in the fractional catabolic rate of LDL, and a two- to three-fold overproduction of LDL . A deficiency of an appropriate receptor for LDL could explain the low fractional catabolic rate of LDL in FH since fibroblasts, lymphocytes, leukocytes and smooth muscle cells could all have an important role in LDL catabolism . It is not possible at present to explain the increased rate of synthesis of apoB in homozygotes . Although a preliminary report (27) suggests direct synthesis of LDL in a homozygote FH, most studies support the view that LDL is derived from the VLDL which is synthesized in the liver or intestine . Further studies of the role of these tissues and the factors which regulate synthesis of these lipoprotéins in the subjects with FH are needed to account for the oversynthesis of apoB .
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In summary, the basic defect in familial hypercholesterole®ia appears to be a cell-membrane defect affecting the receptor for LDL . As a result of this defect, there is altered LDL catabolism which accounts for the low fractional catabolic rate of LDL clearance, and increased levels of LDL resulting in the hypercholesterolemia . MANAGEMENT OF FH The basic medical treatment of choice for heterozygous subjects with FH is similar to that for any patient with type II hyperlipoproteinemia and involves reducing dietary cholesterol (<300 mg/day), restricting saturated fat and increasing polyunsaturated fat. Usually, FH patients respond only aodestly to dietary regimen, and normal plasma lipid levels are seldom achieved . Consequently, pharmacologic agents have been used to obtain maximum reduction of the hypercholesterolemia . The major drugs which have been used are cholestyramine, nicotinic acid and cholesterol . With the exception of nicoIn a doubletinic acid, all of these drugs are bile-acid binding resins . blind trial in patients with type II hyperlipoprotein~ia, Levy et al . (40) found that cholestyramine (16 g/day) significantly lowered the plasma levels of cholesterol and of LDL-cholesterol from means of 333 t 54 mg/dl and 265 f 49 mg/dl, respectively, to 264 t 45 mg/dl and 193 ± 45 mg/dl . Recent followup studies (41,42) in the same group of patients have confirmed the effectiveWhile the combination ness of cholestyramine in lowering plasma cholesterol . of diet and drug therapy are usually effective in lowering cholesterol in subjects with heterozygous FH, more effective measures are required for the homozygous subject ; the additional methods have included plasma exchange and surgical treatment by portacaval shunt or deal bypass . In 1973, Starzl and coworkers (43) were the first to show a dramatic decrease in plasma LDL levels in an FH subject after an end-to-side portacaval shunt . The patient was a 12-year-old girl who was unresponsive to diet or drug therapy . Before surgery, her mean plasma cholesterol level was 769 mg/dl . Subsequent to end-to-side portacaval shunt, there was a striking reduction in total plasma cholesterol to 450 mg/dl . In addition, there was resorption of the tendinous and cutaneous xanthomas and apparent regression of cardiovascular disease with relief of angina and reversal of aortic stenosis . In a follow-up study (44), the 10-month postoperative plasma cholesterol level was 343 ± 41 mg/dl . Although there was general improvement in the patient, she suddenly died 18~ months postsurgery (45) ; death was attributed to an acute cardiac arrhythmia . Since this initial report, Stein et al . (46) and Bilheimer et al . (47) have performed five additional pôrtacaval shunts in patients withhômozygous FH . While the results from these few studies are encouraging, they suggest that the portacaval shunt may not be appropriate for all patients with FH . In the study of Stein et al . (46), the cholesterol values in four patients still ranged between 650-700mg/dl postsurgery. The patients of Bilheimer et al . (47) had a plasma cholesterol value before the shunt of 997 mg/dl and 577 mg/dl after surgery. In this study, the fall in total cholesterol was due to approximately a 48$ decrease in LDL synthesis ; also, there was a very slight decrease in the fractional catabolic rate of LDL. Carew et al . (48) and Chase and Morris (49) have performed end-to-side portacaval shunts in swine and have concluded that the primary mechanism for lowering plasma cholesterol in the pig is a decreased rate of LDL synthesis . Whether the drop in cholesterol synthesis affects the rate of LDL synthesis or vice versa is not know . However, Bilheimer et al . (47) did show that the shunt was associated with an elevation of plasmâbile acids and glucagon which in themselves might be related to the altered LDL and cholesterol synthesis . Another surgical procedure which has been proposed as an alternative for the FH patient who is unresponsive to drug or diet is partial deal bypass .
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The rationale of partial ileal bypass is that it interferes with the enterohepatic bile acid cycle, thus, causing a greater conversion of part of the cholesterol pool to bile acids . Buchwald and his coworkers have been the major proponents of this procedure (For review, see ref . 50) . The first partial ileal bypass operation was performed by Buchwald in 1963 . More than 100 patients have now had a bypass operation by these investigators . Over this time, the average plasma cholesterol levels have dropped 40$ from the preoperative period . While the results are encouraging, there is little evidence from these studies that the ileal bypass is any more successful in lowering cholesterol in the FH subject than diet and drug therapy . Thompson and Gotto (51) have attempted to evaluate ileal bypass surgery from the point of view of the physician involved in the management of patients with FH and have concluded that a preoperative trial with cholestyramine should be attempted before surgery. The surgery should also be limited to adults . Since most individuals with FH need treatment as a child, the ileal operation seems of limited value at the present time . Finally, Thompson et al . (52,53) have reported on the therapeutic use of plasma exchange in twosubjects with homozygous FH ; the subjects were also given cholestyramine and clofibrate . The plasma exchanges were performed at approximately three-week intervals and involved exchanging 2-4 liters of each patient's plasma with normal plasma . By this method, the initial plasma cholesterol levels of 700 mg per 100 ml were reduced to and maintained at 200-400 mg per 100 ml, values which usually are found in heterozygous FH . Although the two subjects have only been plasma exchanged for 4-8 months, they both have shown a symptomatic improvement in their prior angina . ACKNOWLEDGEMENTS The authors are indebted to Ms . Debbie Mason for preparation of the manuscript . The work presented in this paper was developed by the Atherosclerosis, Lipids and Lipoproteins section of the National Heart and Blood Vessel Research and Demonstration Center, Baylor College of Medicine, a grant-supported research project of the National Heart, Lung and Blood Institute, National Institutes of Health, Grant No . 17269, by a General Clinical Research Center grant (RR-00350) and by Contract NIH-71-2156 for a Lipid Research Clinic . R . L . Jackson and Louis C . Smith are Established Investigators of the American Heart Association. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 .
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Lifn Sciencna, Vol . 21, pp . 1395-1402 Priated in the II .S .A .
MINIREVIEW FAMILIAL HYPERCHOLESTEROLEMIA : Richard L. Jackson,
DIAGNOSIS, METABOLIC DEPECT AND MANAGEMENT
Louis C . Smith, 0 . David Taunton and Antonio M. Gotto, Jr .
Departments of Medicine and Biochemistry, Baylor College of Medicine and The Methodist Hospital, Houston, Texas 77030
INTRODUCTION Coronary artery disease remains the major cause of death in our society . Slightly under one million people die each year in the United States of some form of cardiovascular disease, with atherosclerosis being the underlying eti ology in the great majority of cases . Hypercholesterolemia has long been known to be one of the major risk factors for premature coronary artery disease . In a study (1,2) of 500 survivors of myocardial infarctions in Seattle, it was estimated that approximately 30$ had some type of familial hyperlipidemia . Three monogenic forms of hyperlipidemia were identified, namely familial hypercholesterolemia, usually manifested as a type II hyperlipoproteinemia phenotype (3), familial endogenous hypertriglyceridemia, usually presenting as a type IV hyperlipoproteinemia phenotype and familial combined hyperlipidemia which may have a type IIb, IV or even a IIa pattern. Other groups of individuals had polygenic or sporadic hypercholesterole~ia . In a general population of middle-aged adults with plasma cholesterol values of 265 mg/dl or greater, and with triglyceride values less than 300 mg/dl, perhaps only 5$ or less of these individuals with elevated lipids will have a monogenic form of familial hypercholesterolemia (PH) (2,4-6) . Due to the work of several laboratories and especially to that of Brown and Goldstein (7-10), a great deal of information has evolved over the past three years from studies of patients with FH . Because of its potential rele vance to the understanding of the metabolism of cholesterol and low density lipoproteins (LDL) in man, it is appropriate to review the current state of knowledge concerning the diagnosis, the clinical manifestations, the metabolic defect and the management of this interesting form of dyslipidemia . DIAGNOSIS OF FH Familial hypercholesterolemia is a monogenic autosomal-dominant disorder, which is characterized by hypercholesterolemia due to increased plasma low density lipoproteins (LDL), xanthomatous lesions skin and tendons, and a family history of hypercholesterolemia, xanthomatosis aid premature coronary artery disease (3) . The disorder occurs in approximately 1 in 200 to 1 in 500 in the general population (2-6) . In patients with heterozygous FH, there is approximately a two-fold elevation above normal values of LDL-cholesterol from birth; the plasma cholesterol level usually reaches 300 to 500 mg/dl by adulthood . In the rare subjects who are homozygous for the FH gene, the clinical manifestations are much more severe with total plasma cholesterol from 500 to
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1000 mg/dl . In families at risk, the condition may be recognized at birth by analysis of umbilical cord blood. While the homozygotes for FH can be identified by specific biochemical tests performed on fibroblasts grown in tissue culture, there is no definitive cellular marker for the heterozygous at the present time . An elevation of cholesterol or LDL early in life or even at birth is probably the best diagnostic criterion at the present time . The minimum characteristics for the diagnosis of homozygous FH include plasma cholesterol levels in excess of 500 mg/dl, hypercholesterolemia in both parents or in both family lines if the parents are deceased and the appearance of xanthomas in the first decade of life . Many children with homozygous FH have atherosclerosis and die of coronary vascular disease before the age of 20 . The prognosis for the homozygote to reach adulthood is poor, the main cause of death being coronary artery disease . Atherosclerosis affects the coronary, peripheral and cerebral arteries of the homozygote . It is not uncommon in the homozygote for aortic cholesteryl ester deposits to cause aortic valvular stenosis . Whereas corneal arcus and cutaneous deposits of cholesteryl ester occur frequently by adulthood in heterozygotes, they occur in childhood in homozygotes . Homozygous children have yellowish deposits (planar xanthomas) over They also develop tendinous xanthomas and dethe buttocks, knees and elbows . posits around the eyelids known as xanthelasma, both of which are found frequently in heterozygous adults . These cutaneous findings are helpful but are not absolutely diagnostic of FH ; a family history is required for an unambiguous diagnosis . Most individuals with hypercholesterolemia have a type IIa or IIb pattern by the criteria of the World Health Organization's system of lipoprotein typing (11) . In type IIa, LDL-cholesterol is increased but triglycerides and VLDL are normal . In type IIb, LDL-cholesterol, VLDL and triglycerides are all The FH subjects can usually be distinguished by higher cholesterol increased . values, by the appearance of tendinous xanthomas at an early age and by a family genetic analysis . As reviewed recently by Brown and Goldstein (12), there have been more than 325 families with well-documented FH described to date ; most PH are type IIa. From these analyses, it has been concluded that the disorder is transmitted as an autosomal dominant monogenic trait . There is at least one diverging view, viz ., that of Jensen and Blankenhorn (13) who suggest the trait is polygenic rather than monogenic. DEFECT IN FH The primary defect in both heterozygous and homozygous foams of FH which can account for the elevated levels of cholesterol and LDL has been investi-. Normal LDL gated through studies of LDL structure, synthesis and catabolism . contains approximately 35$ cholesteryl ester, 10$ unesterified cholesterol, 5~ Most studies have shown very triglyceride, 25$ protein and 25$ phospholipid . Mills et al . little difference between the LDL of normal and FH subjects . (14) have studied two patients with homozygous FH and were unable tofind any major differences in carbohydrate, phospholipid and fatty acid content ; the LDL from the FH subject did, however, have a slightly higher proportion of The molecular cholesterol and a corresponding lower amount of triglyceride . weights and diffusion constants of the LDL were within normal ranges . There is no detectable difference in the amino acid compositions of the LDL protein Lee and Breckenridge (18) have (apoB) between normal and FH subjects (15-17) . also examined the carbohydrate composition of glycopeptides derived from apoB for normal and heterozygous FH and have not found any differences . Cholesterol balance studies and measurement of total fecal endogenous steroids have provided no evidence for an increased rate of cholesterol synthesis in FH (19) . There is also no evidence for an increased absorption of dietary cholesterol (20) . Furthermore, Myant et al . (21) have been unable
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to demonstrate any significant difference in the absolute rates of turnover of LDL-cholesteryl esters in normals and FH heterozygotes . There was, however, a diminished fractional rate of turnover of LDL-cholesteryl esters (21) . The homozygous FH patient has a fractional rate of turnover of LDL-cholesteryl esters about one-half that of the heterozygotes and about one-third that of norThe absolute rate of turnover for all subjects was the same . The mals (21) . lower fractional catabolic rate of turnover in the hamozygote is undoubtedly related to the elevated plasma LDL. Since the cholesterol balance studies have failed to explain the hypercholesterolemia in FH, more recent studies have focused on the metabolism of LDL-protein or apoB . Longer et al . (22) first showed that the fractional catabolic rate of plasma LDL-protéinin 10 heterozygous patients was decreased nearly 50 percent compared to normals. Consequently, the half-life of LDLprotein was significantly prolonged (3 .1 days for normals compared to 4 .7 for type II subjects) ; the absolute catabolic rate for apoB was normal in this study (22) . Packard et al . (23) have re-examined the metabolic fate of LDL in the heterozygotes andconfirmed that the fractional catabolic rate is decreased (0 .164 for the FH subjects compared to 0.312 for normals) . Packard et al . (23) also reported that the FH heterozygote has a 37~ increase in apoprotéin synthesis compared to normals . In the study of Longer et al . (22), the subjects were maintained in a metabolic ward and were fed adiet containing <300 mg of cholesterol/day and high in polyunsaturated fat (P/S, 2 .5) . Packard et al . (23) followed their subjects as out-patients with no modification in their life style and usual diet . The increased synthesis of apoB in FH has also been shown in homozygotes . Simons and coworkers (24,25) found that the fractional catabolic rate is significantly prolonged for homozygotes (0 .175/day as compared to 0 .497 for nor mals) and that the synthesis of apoB is considerably increased in the homozygote . In this study, the subjects ate a diet containing approximately 300 mg cholesterol/day and a polyunsaturated/saturated fat ratio of 2 :1 . The origin of the increased plasma apoB in the homozygote is an important question which needs further study. As reviewed by Eisenberg and Levy (26), most of the plasma apoB in man is derived from the catabolism of chylomicrons and very low density lipoproteins (VLDL) . However, in a preliminary communication, Thompson et al . (27) have simultaneously measured the turnover of apoB in VLDL and LDL two homozygous subjects and have shown that the rate of synthesis of apoB exceeded that of the apoB in VLDL . These results were interpreted as evidence that apoB is derived not only from VLDL but may also be secreted directly into the plasma as LDL .
in
In summary, there is both a reduced fractional catabolic rate of LDL and an increased rate of LDL synthesis in the subject with homozygous familial hypercholesterolemia . How can both abnormalities be explained by a singlé ge netic defect which can also account for the monogenicity of the inheritance? As a background for discussing the nature of the catabolic defect in FH, a brief review of normal LDL metabolism is appropriate . Much of the information for LDL catabolism stems from the elegant work of Brown and Goldstein . Their studies [for detailed references, see review articles (7-10)] have delineated a receptor-mediated process by which cultured fibroblasts from normal subjects bind and take up LDL through the mechanism of absorptive endocytosis . According to these authors (7-10), the first critical step in LDL catabolism is its binding to a high-affinity specific plasma membrane receptor ; the binding is stoichiometric . Subsequent to binding, LDL is taken up as a receptorbound LDL into the cell by endocytosis, an energy-dependent process . The internalized LDL fuse with lysosomal vesicles and the cholesteryl esters and
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protein are hydrolyzed to free cholesterol and amino acids . As a result of intracellular cholesterol accumulation, three important events occur . First, there is a reduction in new cholesterol synthesis through the suppression of 3hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase activity . Since this enzyme is one of the rate-limiting steps in the cholesterol biosynthetic pathway, .the rate of synthesis of this sterol declines . Secondly, there is activation of acyl-CoA cholesterol acyltransferase ; thus, some of the cholesterol which is taken up is stored as the ester until it can be further utilized . Finally, when sufficient cellular cholesterol has accumulated, the synthesis of the specific LDL receptor is suppressed . Since the accumulation of LDL requires its receptor for high-affinity uptake, there is a block in further cholesterol transport into the call . In addition to the cultured human fibroblast, Ho et al . (28) and Reichl et al . (29) have shown thât the circulating human lymphocyte also has the capacity to produce a high affinity LDL receptor that mediates the cellular uptake and degradation of LDL. Although they have been less well studied, there is evidence that arterial smooth muscle cells (9,30-32) and leukocytes (33-39) may also regulate cellular cholesterol levels through an LDL receptor . All of these studies support the proposal that non-hepatic tissues constitute a major site for LDL degra dation . An important study which lends support to the role of non-hepatic tissues in LDL degradation has been described by Sniderman et al . (36) . They found that the hepatectomized pig has a greater fractional râtéof plasma LDL degradation than does the intact animal (0 .0764 compared to 0.0457 for the same animals before hepatectomy) . If the extrahepatic tissues are responsible for degradation of LDL, how do FH subjects take up and degrade LDL7 Brown and Goldstein (7-10), Khachadurian et al . (37), Fogelman et al . (33,34), Avigan et al . (38) and Breslow et al .(39) have all suggested that there is a metabolicdefect in the FH subject which results in inability of FH cells to suppress HMG-CoA reductase . Studies by Brown and Goldstein (710) have shown that the failure of LDL to suppress HMG-CoA reductase is actually a secondary effect with the primary one being in the binding of the lipoprotein. Brown and Goldstein have defined two types of mutant cells in patients with FH, either receptor-negative or receptor-defective . In the receptor-negative subject, there are no receptors and, consequently, the cells are unable to bind, internalize and degrade LDL normally . Patients with receptor-negative cells have apparently inherited two defective alleles at the receptor locus . In receptor-defective cells, there is binding and uptake of LDL by a specific high affinity receptor but only to about 10$ of normal . Although patients with heterozygous FH have a 50 percent reduction in LDL receptors, the absolute rates of cholesterol production and LDL degradation are normal . Heterozygotes presumably have one normal and one defective allele for binding. Brown and Goldstein (8) have suggested that the absence of receptors or defective receptors in the subject with homozygous FH is associated with three metabolic consequences . These are a high level of plasma cholesterol, primarily as LDL; a three-fold reduction in the fractional catabolic rate of LDL, and a two- to three-fold overproduction of LDL . A deficiency of an appropriate receptor for LDL could explain the low fractional catabolic rate of LDL in FH since fibroblasts, lymphocytes, leukocytes and smooth muscle cells could all have an important role in LDL catabolism . It is not possible at present to explain the increased rate of synthesis of apoB in homozygotes . Although a preliminary report (27) suggests direct synthesis of LDL in a homozygote FH, most studies support the view that LDL is derived from the VLDL which is synthesized in the liver or intestine . Further studies of the role of these tissues and the factors which regulate synthesis of these lipoprotéins in the subjects with FH are needed to account for the oversynthesis of apoB .
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In summary, the basic defect in familial hypercholesterole®ia appears to be a cell-membrane defect affecting the receptor for LDL . As a result of this defect, there is altered LDL catabolism which accounts for the low fractional catabolic rate of LDL clearance, and increased levels of LDL resulting in the hypercholesterolemia . MANAGEMENT OF FH The basic medical treatment of choice for heterozygous subjects with FH is similar to that for any patient with type II hyperlipoproteinemia and involves reducing dietary cholesterol (<300 mg/day), restricting saturated fat and increasing polyunsaturated fat. Usually, FH patients respond only aodestly to dietary regimen, and normal plasma lipid levels are seldom achieved . Consequently, pharmacologic agents have been used to obtain maximum reduction of the hypercholesterolemia . The major drugs which have been used are cholestyramine, nicotinic acid and cholesterol . With the exception of nicoIn a doubletinic acid, all of these drugs are bile-acid binding resins . blind trial in patients with type II hyperlipoprotein~ia, Levy et al . (40) found that cholestyramine (16 g/day) significantly lowered the plasma levels of cholesterol and of LDL-cholesterol from means of 333 t 54 mg/dl and 265 f 49 mg/dl, respectively, to 264 t 45 mg/dl and 193 ± 45 mg/dl . Recent followup studies (41,42) in the same group of patients have confirmed the effectiveWhile the combination ness of cholestyramine in lowering plasma cholesterol . of diet and drug therapy are usually effective in lowering cholesterol in subjects with heterozygous FH, more effective measures are required for the homozygous subject ; the additional methods have included plasma exchange and surgical treatment by portacaval shunt or deal bypass . In 1973, Starzl and coworkers (43) were the first to show a dramatic decrease in plasma LDL levels in an FH subject after an end-to-side portacaval shunt . The patient was a 12-year-old girl who was unresponsive to diet or drug therapy . Before surgery, her mean plasma cholesterol level was 769 mg/dl . Subsequent to end-to-side portacaval shunt, there was a striking reduction in total plasma cholesterol to 450 mg/dl . In addition, there was resorption of the tendinous and cutaneous xanthomas and apparent regression of cardiovascular disease with relief of angina and reversal of aortic stenosis . In a follow-up study (44), the 10-month postoperative plasma cholesterol level was 343 ± 41 mg/dl . Although there was general improvement in the patient, she suddenly died 18~ months postsurgery (45) ; death was attributed to an acute cardiac arrhythmia . Since this initial report, Stein et al . (46) and Bilheimer et al . (47) have performed five additional pôrtacaval shunts in patients withhômozygous FH . While the results from these few studies are encouraging, they suggest that the portacaval shunt may not be appropriate for all patients with FH . In the study of Stein et al . (46), the cholesterol values in four patients still ranged between 650-700mg/dl postsurgery. The patients of Bilheimer et al . (47) had a plasma cholesterol value before the shunt of 997 mg/dl and 577 mg/dl after surgery. In this study, the fall in total cholesterol was due to approximately a 48$ decrease in LDL synthesis ; also, there was a very slight decrease in the fractional catabolic rate of LDL. Carew et al . (48) and Chase and Morris (49) have performed end-to-side portacaval shunts in swine and have concluded that the primary mechanism for lowering plasma cholesterol in the pig is a decreased rate of LDL synthesis . Whether the drop in cholesterol synthesis affects the rate of LDL synthesis or vice versa is not know . However, Bilheimer et al . (47) did show that the shunt was associated with an elevation of plasmâbile acids and glucagon which in themselves might be related to the altered LDL and cholesterol synthesis . Another surgical procedure which has been proposed as an alternative for the FH patient who is unresponsive to drug or diet is partial deal bypass .
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The rationale of partial ileal bypass is that it interferes with the enterohepatic bile acid cycle, thus, causing a greater conversion of part of the cholesterol pool to bile acids . Buchwald and his coworkers have been the major proponents of this procedure (For review, see ref . 50) . The first partial ileal bypass operation was performed by Buchwald in 1963 . More than 100 patients have now had a bypass operation by these investigators . Over this time, the average plasma cholesterol levels have dropped 40$ from the preoperative period . While the results are encouraging, there is little evidence from these studies that the ileal bypass is any more successful in lowering cholesterol in the FH subject than diet and drug therapy . Thompson and Gotto (51) have attempted to evaluate ileal bypass surgery from the point of view of the physician involved in the management of patients with FH and have concluded that a preoperative trial with cholestyramine should be attempted before surgery. The surgery should also be limited to adults . Since most individuals with FH need treatment as a child, the ileal operation seems of limited value at the present time . Finally, Thompson et al . (52,53) have reported on the therapeutic use of plasma exchange in twosubjects with homozygous FH ; the subjects were also given cholestyramine and clofibrate . The plasma exchanges were performed at approximately three-week intervals and involved exchanging 2-4 liters of each patient's plasma with normal plasma . By this method, the initial plasma cholesterol levels of 700 mg per 100 ml were reduced to and maintained at 200-400 mg per 100 ml, values which usually are found in heterozygous FH . Although the two subjects have only been plasma exchanged for 4-8 months, they both have shown a symptomatic improvement in their prior angina . ACKNOWLEDGEMENTS The authors are indebted to Ms . Debbie Mason for preparation of the manuscript . The work presented in this paper was developed by the Atherosclerosis, Lipids and Lipoproteins section of the National Heart and Blood Vessel Research and Demonstration Center, Baylor College of Medicine, a grant-supported research project of the National Heart, Lung and Blood Institute, National Institutes of Health, Grant No . 17269, by a General Clinical Research Center grant (RR-00350) and by Contract NIH-71-2156 for a Lipid Research Clinic . R . L . Jackson and Louis C . Smith are Established Investigators of the American Heart Association. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 .
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