417
Atherosclerosis, 28 (1977) 417-423 0 Elsevier/North-Holland Scientific Publishers, Ltd.
SERUM LIPIDS AND CORONARY HEART DISEASE IN HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA HOKURIKU DISTRICT OF JAPAN
IN THE
H. MABUCHI, T. HABA, K. UEDA, R. UEDA, R. TATAMI, S. ITO, T. KAMETANI, J. KOIZUMI, S. MIYAMOTO, M. OHTA, R. TAKEDA, T. TAKEGOSHI and H. TAKESHITA Second Department of Internal Medicine, School of Medicine, Kanazawa University, and the Section of Internal Medicine, Hokuriku Hospital, Kanazawa, and the Section of Internal Medicine, Fukui Prefectural Hospital, Fukui (Japan) (Received 1 August, 1977) (Accepted 26 August, 1977)
Summary The serum cholesterol and triglyceride levels and the incidence of ischemic heart disease were studied in 122 (55 men and 67 women) consecutive heterozygous familial hypercholesterolemic patients in the Hokuriku district of Japan. (1) The mean f SD of serum cholesterol level was 354.0 + 71.0 mg/lOO ml, which was lower than those of the Western countries by about 60--70 mg/ 100 ml. (2) The mean f SD of serum triglyceride level was 116.5 f 54.0 mg/lOO ml. (3) The average serum cholesterol values in the 20-50-year-old group showed no differences from those of the Western countries. However, in the above 50 years of age group the serum cholesterol levels were much lower than those in the United States. (4) The occurrence of ischemic heart disease in 83 heterozygous familial hypercholesterolemic patients was 43.3%. The incidence of myocardial infarction was 20.5%. Thus, familial hypercholesterolemia is as highly atherogenic as that of the Western countries even in Japan where the low incidence of coronary heart disease in the general population has been attributed to the low level of serum cholesterol. Key words:
Serum lipids - Coronary terolemia - Japan
heart disease - Heterozygous
familial hypercholes-
418
Fig. 1. The Hokuriku district of Japan.
Introduction Hypercholesterolemia is one of the major risk factors of ischemic heart disease [ 121. Populations with a high average level of serum cholesterol tend to have high mortality rates of coronary heart disease [3]. The low incidence of ischemic heart disease in Japan has been attributed to the low level of serum cholesterol [ 41. A variety of biological variables may influence the serum cholesterol level [l]. Racial groups that have been observed in different countries with varying dietary fat content have serum cholesterol values that correlate with the fat intake [ 51. Familial hypercholesterolemia is an inherited disorder characterized by hypercholesterolemia due to hyperbetalipoproteinemia, together with xanthomatous lesions in the skin or tendons, and premature atherosclerotic heart disease [1,2]. The disease is not confined to any country or racial group, and it is reported to occur in North America, the Western countries, Lebanon, Australia and Japan [ 11. In familial hypercholesterolemic patients, as well as the general population, the serum cholesterol level is influenced by dietary and environmental factors [ 1,6]. In this report we examine whether Japanese patients with familial hypercholesterolemia have any special characteristics in their serum lipid levels and incidence of coronary artery disease compared with those in the Western countries. For this purpose the serum cholesterol and triglyceride levels were determined together with a clinical evaluation of coronary artery disease in 122 patients with heterozygous familial hypercholesterolemia living in the Hokuriku district of Japan (Fig. 1). Materials and methods Familial hypercholesterolemic patients were selected according to the following 2 criteria: (1) primary hypercholesterolemic patients (arbitrarily above 220 mg/ml in any age group) with tendon xanthomas; (2) primary hypercholesterolemic patients with and without tendon xanthomas in a first degree relative of familial hypercholesterolemic patients. All these cases showed hyper-fl- (IIa) or hyper-/3- and hyper-pre-fl- (IIb)
419
lipoproteinemias by agarose gel electrophoresis according to the method of Noble [7]. Tendon xanthomas were detected by examination of X-rays of the Achilles’ tendon [ 81. The normal 95 percentile of Achilles’ tendon thickness is 8.6 mm in the Japanese [9] : those patients with Achilles’ tendons greater than 9 mm in thickness were thought to have tendon xanthomas [9]. Seven of the familial hypercholesterolemic patients were suspected of homozygous familial hypercholesterolemia, because of the early onset of severe xanthomatosis and/or heterozygous familial hypercholesterolemia in both parents [l]. All other 122 cases studied in this report were heterozygous. Normal subjects were those who had no disease associated with lipid metabolism. The diagnosis of coronary artery disease was made on the basis of the presence of one or more of the following symptoms: (1) angina pectoris; (2) myocardial infarction documented by the serum GOT or CPK elevation with appearance of electrocardiographic signs of coronary insufficiency and necrosis evaluated according to the Minnesota Code [lo]. Blood samples were drawn from an arm vein after the patients had fasted for 12 h. The blood was left to clot at room temperature for 2 h and then centrifuged at 3000 rev/min for 20 min. Total serum cholesterol was measured according to the enzymatic method [ 111. Serum triglyceride was measured by the method of Fletcher [ 121. Results (I) Sex and age distribution In the total of 122 heterozygous familial hypercholesterolemic patients, 55 were men and 67 were women. Age distribution was 3.9% under 10 years; 6.2% between the ages of lo-19 years; 21.7% between the ages of 20-29 years; 17.8% between the ages of 30-39 years; 10.1% between the ages of 40-49 years; 20.2% between the ages of 50-59 years; and 15.5% over 60 years. The mean and standard deviation of age was 41.3 f 16.8 years. (2) Fasting serum lipids in heterozygous familial hypercholesterolemia (Table 1) The mean (*SD) of serum cholesterol was 354.0 (k71.0) mg/lOO ml. The mean (*SD) of serum triglyceride was 116.5 (~~54.0) mg/lOO ml. One hundred and eleven cases showed hyper-@-lipoproteinemia (IIa) and 11 cases showed
TABLE 1 SERUM CHOLESTEROL CHOLESTEROLEMIA
AND TRIGLYCERIDE
LEVELS
IN HETEROZYGOUS
FAMILIAL
HYPER-
Lipid
Men (n: 54)
women (n: 68)
Total (n: 122)
Patients’ age (years) Serum cholesterol (mg/lOO ml) Serum triglyceride (mg/lOO ml)
40 k168 342.7 f 80.4 a 129.1 + 62.7 a
43 f18 363.1 f 61.7 106.7 f 53.4
41 +17 354.0 ? 71.0 116.5 f 54.0
aMeanf
SD.
420
HOKURIKU (JAMN)
AGE
(yun
OldI
Fig. 2. Average serum cholesterol values (mean f SD) by age groups in 122 cases of heterozygous familial hypercholesterolemia in the Hokuriku district of Japan and in 262 cases of heterozygous familial hyper cholesterolemia in the United States [l].
hyper-/3- and hyper-pre-fl-lipoproteinemia (IIb). The mean (*SD) of serum cholesterol and triglyceride levels in the normal 119 subjects were 186.7 (k29.7) mg/lOO ml and 102.1 (k40.9) mg/lOO ml, respectively. (3) Se&m cholesterol values by age group The average serum cholesterol levels for each age group are shown in Fig. 2. The serum cholesterol level in the youngest age group was higher than that in the United States [l]. The average cholesterol values in the 20--50-year-old group did not differ from that in the United States [ 11. However, in the above 50 years of age group, the serum cholesterol levels in Japanese familial hypercholesterolemic patients were much lower than those in the United States [ 11. (4) The frequency distribution of serum cholesterol and triglyceride values The frequency distribution of serum cholesterol values showed a distinct bimodality for the normal and familial hypercholesterolemia (Fig. 3). A considerable overlap between the scattergram for heterozygous familial hyper-
SERUM CHOLE.STEROL
( mg/,wnl I
SERUM TRIGLYCERIDE
( mg/mml 1
Fig. 3. The distribution of serum cholesterol concentrations terolemic patients.
in normal subjects and familial hypercholes-
Fig. 4. The distribution of serum triglyceride concentrations terolemic patients.
in normal subjects and familial hypercholes-
421 TABLE 2 ISCHEMIC HEART DISEASE IN HETEROZYGOUS
FAMILIAL
HYPERCHOLESTEROLEMIA
Patients
Men (n: 37)
Women (n: 46)
Total (n: 83)
Mean age (years) Coronary insufficiency Myocardhl infarction Normal ECG
42 Sa 12 20
43 14 6 27
19 17 41
a Number of patients.
cholesterolemic and normal 8UbjeCt8was found for value8 from 220 to 270 mg/lOO ml. There was no significant difference between familial hypercholesterolemic and normal subjects with respect to the triglyceride value8 (Fig. 4). The frequency distribution for triglyceride concentration8 showed no bimodality , (5) Coronary heart disease in heterozygous familial hypercholesterolemia (Table 2) The occurrence of coronary artery disease in 83 familial hypercholesterolemic patient8 was 43.3% (36 cases). The occurrence of myocardial infarction was 20.5% (17 cases). Di8CU88iOn
Familial hypercholesterolemia (Type II hyperlipoproteinemia) is a wellrecognized clinical entity caused by a genetic defect and transmitted as an autosomal ‘dominant of nearly complete penetrance [1,13]. It occurs in approximately 1 in 500 person8 in the general population of the United States [1,13]. The incidence of the disease in Japan is unknown. In the present study we found 3 familial hypercholesterolemic patient8 (0.11%) out of 2700 consecutive new outpatient8 in our clinics. Goldstein and hi8 coworker8 suggested that the metabolic abnormalities observed in familial hypercholesterolemia may be caused by a defect in the specific LDL-receptor [13]. Therefore, proving a defect of the LDL-receptor in the cultured skin fibroblasts [ 141 or freshly obtained lymphocytes [ 151 may be essential for the diagnosis of familial hypercholesterolemia. Clinically, the disorder is diagnosed by the triad for familial hypercholesterolemia: hyperP-lipoproteinemia, typical abnormality in blood relatives, and tendon xanthomas [ 11. Tendon xanthoma, which is a specific physical finding for familial hypercholesterolemia [ 11, and latent xanthomas are evaluated only by X-ray of the Achilles tendon8 [B]. Thus, an abnormally thick Achilles’ tendon is a specific sign for the diagnosis of familial hypercholesterolemia [ 91. The serum lipid levels in familial hypercholesterolemia, as well as in the general population, are under genetic and environmental influences [l]. Consequently, a diet restricted in cholesterol and saturated fats and enriched in polyunsaturate8 lowers the cholesterol levels in familial hypercholesterolemic patients [6]. In Japan, where the serum cholesterol level in the general popula-
422
tion is much lower than that in Western countries [4], the mean serum cholesterol and triglyceride levels in the familial hypercholesterolemic patients were lower than those in the United States by 60-70 mg/lOO ml and 15-20 mg/ 100 ml, respectively [ 11. However, in the patient group of under 50 years of age, the cholesterol levels showed the same average value as those in familial hypercholesterolemia in the United States [ 11, although the levels were lower than those in two European countries by 60-110 mg/lOO ml [16,17]. The average serum cholesterol values in 110 patients with essential familial hypercholesterolemia in Danish families were higher than the values in Japan by more than 100 mg/lOO ml [ 161. From these data the cut-off points used in the United States are applicable to detect heterozygotes among Japanese below 50 years of age, although they are too high for older Japanese heterozygotes. The mean daily fat intake in Japan increased from 16 g (6.9% of total calorie) in 1949 to 52 g (21.2%) in 1974 [18]. This increase in fat intake may contribute to the higher cholesterol levels in Japanese heterozygotes in the age group under 50 years, although the cholesterol levels in the general population are still low in this country. Older people in Japan perhaps are still following the traditional Japanese dietary habits. There is evidence that Japanese-American men in Hawaii followed a more Japanese life style until World War II; American habits - particularly eating habits - were adopted later [ 191. In a recent report, the mean values of serum cholesterol were lower in Japanese in Japan compared with Japanese in Hawaii, although the samples were collected only in 45-68-year-old males [20]. It is notable that, in comparing Framingham and Honolulu, the risk of coronary heart disease in young Japanese men in Honolulu was much closer to that of Framingham, than was the case with the older men
1211. The incidence of ischemic heart disease in Japan is at present much lower than that of Western countries and this low incidence has been attributed to the low serum cholesterol level in this country [4]. However, in Japanese familial hypercholesterolemic patients whose serum cholesterol levels are close to those of familial hypercholesterolemic patients in the United States, the incidence of ischemic heart disease was 43.3% and was higher than that reported from the National Institutes of Health, Bethesda, Md. [22], although lower than that reported by Beaumont et al. [17]. From the present study it is anticipated that the incidence of coronary heart disease in Japan may become as high as in the United States and other Western countries if the serum cholesterol level increases to Western levels through changes in dietary habits. References Fredrickson, D.S. and Levy, R.I., Familial hyperlipoproteinemia. In: J.B. Stanbury. J.B. Wywaarden and D.S. Fredrickson (Ed%). The Metabolic Basis of Inherited Disease, 3rd ed., McGraw-Hill. New York, 1972, P. 631. Fredrickson, D.S.. Levy, R.I. and Lees, R.S.. Fat transport in lipoproteins -An integrated approach to mechanisms and disorders, New En& J. Med., 276 (1967) 32.94.148.216.273. Kannel. W.B., Castelli. W.P., Gordon, T. and McNamara, P.M., Serum cholesterol, lipoproteins. and the risk of coronary heart disease, Ann. intern. Med., 74 (1971) 1. Keys, A., Coronary heart disease in seven countries, Circulation, 41. Suppl. l(l970) 162. Kato. H.. TUlotson, J., Nichsman, M.Z., Rhoads. G.G. and Hamilton, H.B., Epidemiologic studies of
423 coronary
heart disease and stroke in Japanese
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(1968) 393. Goldstein, J.L. and Brown, B.S., Familial hypercholesterolemia. A genetic regulatory defect in cholesterol metabolism. Amer. J. Med.. 58 (1975) 147. Brown, M.S. and Goldstein, J.L., Familial hypercholesterolemia. Defective binding of lipoproteins to cultured ilbroblasts associated with impaired regulation of 3-hydroxy-3methylglutaryl coenzyme A reductase activity, Proc. Natl. Acad. Sci. (USA). 71 (1974) 788. Ho. Y.K.. Brown, M.S., Bilhelmer, D.W. and Goldstein, J.L.. Regulation of low density lipoprotein receptor activity in freshly isolated human lymphocytes, J. Clin. Invest., 58 (1976) 1465. Piper, J. and Orrlld. L., Essential familial hypercholesterolemia and xanthomatosis. Follow-UP study of twelve Danish famllles. Amer. J. Med., 21 (1956) 34. Beaumont, V.. Jacotot, B. and Beaumont. J.L., Ischaemic disease in men and women with familial hypercholesterolaemia and xanthomatosls, Atherosclerosis, 24 (1976) 441. Health and Welfare Statics Association, Kosei no Shlhyo. 23 (1976) 372 (Japanese). Kagan. A., Harris. B.R., Winkelsteln, W.. Jr., Johnson, K.G., Kate, H.. Syme, S.L.. Rhoads, G.G., Gay. M.L.. Nichaman, M.Z., Hamilton, H.B. and Tlllotson. J.. Epidemiologic studies in Japanese men living in Japan, Hawaii and California. Demographic, physical, dietary and biochemical characteristics, J. Chron. Dia. 27 (1974) 345. Robertson, T.L.. Kate. H., Gordon, T.. Kagan, A.. Rhoads, G.G.. Land, C.E.. Worth, R.M., Belsky. J.L., Dock, D.S., Miyanlshi, M. and Kawamoto, S.. Epidemiologic studies of coronary heart disease and stroke in Japanese men living ln Japan. Hawaii and California. Coronary heart disease factors in Japan and Hawaii. Amer. J. Cardiol., 39 (1977) 244. Gordon, T.. Garcia-Palmierl. M.R.. Kagan, A., Kannel. W.B. and Schiffman. J., Differences in coronary heart disease in Framingham. Honolulu and Puerto Rico, J. Chron. Dis.. 27 (1974) 329. Stone, N.J., Levy, RI.. Fredrickson. D.S. and Verter, J., Coronary artery disease in 116 klndreds with famlhal type II hyperllpoproteinemia. Circulation, 49 (1974) 476.