Mutations in the low-density lipoprotein receptor gene in Chinese familial hypercholesterolemia patients.

It has been reported that in China, patients with heterozygous familial hypercholesterolemia (FH) may go unrecognized because they do not have xanthomata or premature coronary heart disease and their LDL cholesterol levels are lower than those in their Western counterparts. However, in the Chinese patients in Hong Kong, heterozygous FH appears to manifest in a way similar to that seen in Western countries or Japan. We studied sequence variations in the promoter and coding regions of the 18 exons of the LDL receptor gene in 30 Chinese FH patients. Eighteen mutations were identified in 21 patients scattered in the promoter and 10 exons. Eleven of them were first found in this study. We also found 6 polymorphisms with allelic frequencies different from those in whites but similar to the Japanese, indicating some isolation between white and Oriental populations. A total of 29 mutations in the LDL receptor gene are now known in the Chinese. There is no definite common mutation due to a founder effect. Meanwhile, there were no detectable LDL receptor gene mutations in 9 clinically diagnosed FH patients in whom the R3500Q mutation in apolipoprotein B had also been excluded. The gene defects leading to the FH phenotype in these patients may occur somewhere else in the apolipoprotein B or other related genes, or even in the noncoding sequences of the LDL receptor gene.

Hyperhomocysteinaemia and premature coronary artery disease in the Chinese.

OBJECTIVES: To examine the prevalence of hyperhomocysteinaemia and compare it with the classic risk factors and vitamin status in Hong Kong Chinese patients with premature atherosclerotic coronary artery disease. DESIGN: Case-control study. SETTING: General hospital and community. SUBJECTS: Forty five patients (39 males) with significant coronary artery disease confirmed by angiography (32 post myocardial infarction) and 23 healthy volunteers (17 male), all aged less than 55 years. INTERVENTION: Standardised methionine-loading test. MAIN OUTCOME MEASURES: Coronary artery disease, risk factors. RESULTS: More patients than controls had fasting hyperhomocysteinaemia (10/45 v 2/23, P = 0.122), post-methionine hyperhomocysteinaemia (17/45 v 1/23, P = 0.008), and an abnormal response to methionine (15/45 v 1/23, P = 0.015). A history of smoking was more frequent in patients (3/23 v 25/45, P = 0.002). Sixteen of 17 patients with hyperhomocysteinaemia but only nine of 28 with normohomocysteinaemia were smokers (P = 0.0002). Fasting plasma cholesterol concentrations (mean (SD)) were higher in hyperhomocysteinaemic patients (6.41 (1.58) mmol/l) than in controls (5.53 (0.90) mmol/l) (P = 0.042). Serum vitamin B-12 was not reduced and serum folate was higher in hyperhomocysteinaemic patients (35 (4) nmol/l) than normohomocysteinaemic patients (26 (9) nmol/l) (P = 0.009). CONCLUSIONS: Although the prevalence of hyperhomocysteinaemia in Hong Kong Chinese is similar to that in white subjects, hyperhomocysteinaemia is not an independent risk factor for coronary artery disease and is associated with smoking. This may be of some consequence in view of the change to a more Western diet with more animal protein, and therefore methionine, coupled with a high frequency of cigarette smokers in this region. The causes of the hyperhomocysteinaemia are multifactorial but in this pilot study a deficiency of folate and/or vitamin B-12 did not seem to be one of them.

Urinary excretion of testosterone and estradiol in Chinese men and relationships with serum lipoprotein concentrations.

Urinary excretion of total and free testosterone and estradiol was measured in 46 healthy Chinese men, along with serum concentrations of total testosterone and estradiol and the calculated free (unbound) concentrations. Associations with serum concentrations of total, low-density lipoprotein (LDL), high-density lipoprotein-2 (HDL2), and HDL3 cholesterol, apolipoproteins (apos) A-I and B, lipoprotein(a) [Lp(a)] were studied. Serum total and free testosterone concentrations were positively correlated with HDL and HDL2 cholesterol and apo A-I. Serum total and free estradiol levels showed borderline-significant negative associations with total and LDL cholesterol levels. Among urinary variables, total estradiol excretion was negatively associated with apo B levels and showed borderline-significant associations with total and LDL cholesterol. Adjustment for potential confounders, including age, body mass index (BMI), and waist to hip ratio (WHR), strengthened the associations between urinary total estradiol and serum total cholesterol, LDL cholesterol, and apo B. Urinary free estradiol showed a significant correlation with HDL3 cholesterol. Urinary excretion of total testosterone was significantly negatively associated with serum cholesterol and LDL cholesterol levels only after controlling for confounding variables. There were no significant associations between hormone variables and Lp(a) values. This study suggests that variation in sex hormone production accounts for some of the variation in serum lipid levels.

An examination of the effect of combined cyclical hormone replacement therapy on lipoprotein(a) and other lipoproteins.

Lipoprotein(a) (Lp(a)) is an independent marker of cardiovascular disease which is relatively unresponsive to treatment with most of the commonly prescribed lipid lowering drugs. Concentrations of Lp(a) increase after the menopause, and the primary aim of this study was to determine whether combined hormone replacement therapy was effective in lowering levels of Lp(a) in postmenopausal women. An open longitudinal study was conducted among 42 women who had undergone a spontaneous menopause and were attending the outpatient clinic of the Prince of Wales Hospital, Hong Kong. All subjects were treated with 2 mg oral estradiol daily and 5 mg medroxyprogesterone acetate for 12 days each calendar month. Fasting blood samples for lipoprotein measurement were taken before the commencement of treatment and at 6 and 12 months. Lp(a) levels showed a skewed distribution with a median value before treatment of 9.45 mg/dl (range 1.47-95.62 mg/dl). After 6 months, there was a reduction to 7.70 mg/dl (1.12-72.59 mg/dl) (P < 0.01), and after 12 months the median concentration was 7.14 mg/dl (0.63-69.23 mg/dl) (P < 0.001 0-12 months). There were also significant reductions in the concentrations of apo B from 116.13 to 111.62 mg/dl and LDL-C from 3.02 to 2.74 mmol/l (P < 0.05), plus a lowering of TC of borderline significance. Apo A-I increased from 162.56 to 173.35 mg/dl (P < 0.01), but there were no significant changes in HDL-C or the HDL-C subfractions. TC, LDL-C, apo B and TG concentrations were higher and HDL-C and HDL2-C concentrations were lower when blood was sampled during combined treatment with estrogen and progesterone than when estrogen was being taken alone. Levels of Lp(a) were also lower during the estrogen only phase of treatment, but none of these differences were statistically significant. This study demonstrates that combined cyclical hormone replacement therapy is effective in reducing concentrations of Lp(a). The trend towards a more atherogenic lipid profile during the combined phase of treatment suggests that attention should be given to the timing of blood sampling in future studies of this nature.

The effect of percutaneous oestrogen replacement therapy on Lp(a) and other lipoproteins.

OBJECTIVES: To determine the effect of percutaneous oestrogen replacement therapy on lipoprotein (a) and other plasma lipoproteins. METHODS: Open longitudinal prospective study conducted at the hormone replacement clinic of the Prince of Wales Hospital, New Territories, Hong Kong. Thirty women who had undergone a total abdominal hysterectomy and bilateral salpingo-oophorectomy for benign gynaecological conditions were treated with 1.5 mg of percutaneous 17 beta-oestradiol gel applied daily for a period of 12 consecutive months. Measurements of plasma lipoproteins were made before the commencement of treatment and repeated at 6- and 12-month intervals. RESULTS: There was a significant reduction in the concentrations of Lp(a) during the first 6 months of treatment, with median values falling from 7.87 mg dL-1 to 6.16 mg dL-1 (P = 0.004, 0-6 months). During the second 6 months, the median concentration increased to 9.38 mg dL-1, (P = 0.072, 6-12 months), which did not significantly differ from the baseline level (P = 0.545, 0-12 months). Significant reductions in the concentrations of apoprotein A-I (apo A-I), apoprotein B (apo B), high density lipoprotein cholesterol (HDL-C), and HDL3-C were also present after 6 months (P = 0.043, 0.049, 0.028, 0.013, respectively), but there were no differences between the baseline values of these lipoproteins and those at the completion of the study (P = 0.948, 0.244, 0.839, 0.117 respectively). Drug compliance was maintained throughout the study, with similar mean oestradiol concentrations at 6 and 12 months. CONCLUSIONS: The percutaneous administration of 17 beta-oestradiol has variable short term effects on plasma lipoproteins which are not maintained over a longer duration of treatment. By avoiding the 'first pass' effect on the liver, this method of delivery does not appear to produce the sustained changes in lipoproteins seen with oral treatment.

Effects of fluvastatin on lipid profile and apolipoproteins in Chinese patients with hypercholesterolemia.

The effects of fluvastatin treatment on lipid profile and apolipoproteins were assessed in a group of 31 Chinese patients with hypercholesterolemia, maintained on a constant low-fat diet. Some patients had the additional cardiovascular risk factors of hypertension and non-insulin-dependent diabetes mellitus, and 6 patients had familial hypercholesterolemia. Baseline lipid levels were measured after a 4-week placebo period, and these were repeated after 4 weeks of treatment with fluvastatin 20 mg daily, and after 4 weeks of treatment with fluvastatin 40 mg daily. Total cholesterol, low density lipoprotein cholesterol, and apolipoprotein (apo) B were each reduced to the same extent with the 2 doses of fluvastatin (-20%, -26%, and -20%, respectively). Triglycerides and very low density lipoprotein cholesterol were also reduced by about 12% with the 2 doses of fluvastatin. Apo A-I was increased by 7% and high density lipoprotein cholesterol (HDL-C) was increased by 10% with the 40 mg dose. The increase in HDL-C was due to increases in both HDL2-C (18%) and HDL3-C (7%). Lipoprotein(a) levels did not show any significant change with the 2 doses of fluvastatin in this short-term study. One patient developed reversible asymptomatic elevation of liver enzymes with the higher dose of fluvastatin; otherwise the drug was well tolerated and no patients had to be withdrawn from the study.

IgD multiple myeloma with thoracic spine compression due to epidural extra-osseous tumour spread.

On initial presentation of a patient with IgD multiple myeloma there were no features to suggest an unusual variant. Two months later she developed spinal cord compression due to an IgD plasmacytoma. This complication of IgD myeloma has rarely been reported. During the course of the disease and using the routine laboratory protocol for investigating and identifying paraproteins, including IgD, the patient's results became indistinguishable from those in Bence-Jones proteinuria myeloma.

The combined effects of aerobic exercise and alcohol restriction on blood pressure and serum lipids: a two-way factorial study in sedentary men.

OBJECTIVES: To determine whether vigorous exercise and alcohol restriction have additive and independent effects in reducing blood pressure in sedentary male alcohol drinkers. Also to assess whether 4 weeks of vigorous exercise could offset the fall in high-density lipoprotein cholesterol (HDL-cholesterol) usually observed after alcohol restriction. DESIGN: Seventy-five sedentary men were randomly assigned to drink low-alcohol beer or continue their normal drinking habits. Within these two groups subjects were further assigned either to a vigorous exercise programme of three 30-min sessions a week of cycling at 60-70% of maximum workload or to a control light-exercise programme. RESULTS: Seventy-two subjects completed the trial. Alcohol consumption fell by 85% in the low-alcohol group. Fitness increased by 10% following vigorous exercise, with a significant improvement in maximum oxygen uptake. After adjustment for weight loss, a significant effect of alcohol restriction in reducing both systolic and diastolic blood pressure was demonstrated. There was no effect of vigorous exercise on blood pressure. Serum total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B were not influenced by alcohol restriction or vigorous exercise. However, alcohol restriction significantly reduced triglyceride, HDL-cholesterol, its subfractions HDL2-cholesterol and HDL3-cholesterol, and its major apolipoproteins apo A-I and apo A-II. These reductions were unaffected by moderate exercise. CONCLUSIONS: This study provides further evidence that alcohol restriction results in reductions in blood pressure in men who are regular alcohol drinkers. However, a simultaneous increase in fitness did not lead to lower blood pressures than those achieved with alcohol restriction alone, and was unable to offset alcohol-related falls in HDL-cholesterol, its subfractions and its major apolipoproteins.

Changes in markers of alcohol intake in man below 'safe' drinking levels.

In a group of 343 working men, only 34 of whom regularly drank more than 60 ml of ethanol per day, logistic regression was used to determine the combination of biomarkers which best discriminated between those who regularly drank less than 30 ml or 30 ml or more of ethanol daily. The index consisted of apolipoprotein A-II, uric acid, gamma-glutamyl transpeptidase and mean corpuscular volume. Even with the relatively low level of alcohol intake reported in these subjects (assessed using a 7-day retrospective alcohol diary), the groups with higher or lower intake of alcohol were separated with a sensitivity of 68%, a specificity of 74% and a positive predictive value of 71%. Systolic blood pressure, adjusted for age and body mass index, was also linearly related to alcohol intake, and when included in the biomarker index improved the proportion correctly classified from 71% to 75%. Using the biomarkers only, 94% of subjects regularly drinking at least 80 ml of ethanol equivalent per day and 100% of the non-drinkers were correctly classified.

Effects of alcohol and caloric restrictions on blood pressure and serum lipids in overweight men.

We have examined the independent and combined effects on blood pressure and blood lipids of alcohol restriction and weight loss in overweight male drinkers with a view to assessing overall effects on cardiovascular risk of two widely promoted nonpharmacological approaches for hypertension. Eighty-six men with a mean age of 44.3 years, a mean regular alcohol intake of 440 ml/wk (five or six standard drinks per day), a mean blood pressure of 137.4 mm Hg systolic and 84.8 mm Hg diastolic, and a mean body mass of 92.5 kg entered a controlled two-way factorial study. The subjects were randomly assigned to four groups for an 18-week intervention in which members of two groups drank only low-alcohol beer, thereby reducing their alcohol intake by 374 ml/wk, while those of the other two groups continued their normal alcohol intake. Within the low and normal alcohol intake groups subjects either continued their usual diet or reduced their caloric intake by 4,200-6,300 kJ/day (1,000-1,500 kcal/day) (with protein, fat, and carbohydrate provided as 15%, 30%, and 55% of total calories, respectively). Calorie reduction and alcohol restriction caused weight losses of 7.5 (p less than 0.001) and 2.1 (p less than 0.01) kg, respectively. Calorie reduction and alcohol restriction were associated with decreases in systolic blood pressure of 5.4 (p less than 0.001) and 4.8 (p less than 0.01) mm Hg, respectively, and in diastolic blood pressure of 4.2 (p less than 0.001) and 3.3 (p less than 0.01) mm Hg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of smoking cessation on serum apolipoprotein A-I and A-II concentrations.

This study investigated the effects of 6 weeks' smoking cessation on serum levels of total-cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C) and apolipoproteins A-I and A-II (apo A-I and apo A-II) in 64 subjects of both sexes. Smoking cessation was associated with an increase in levels of apo A-II. Concurrent changes in weight and alcohol consumption during attempted smoking cessation, together with change in thiocyanate level, were entered as predictor variables into a multiple regression analysis. The change in apo A-II was found to be best accounted for by change in plasma thiocyanate level, and, in women, change in HDL-C and apo A-I by change in weight. The changes induced by smoking cessation may be due, at least in part, to associated changes in alcohol consumption and/or dietary intake, but in the case of apo A-II there is evidence of a more direct effect.

Comparison of diets supplemented with fish oil or olive oil on plasma lipoproteins in insulin-dependent diabetics.

This study was designed to compare changes in high-density lipoprotein (HDL)- and low-density lipoprotein (LDL)-cholesterol in normolipidaemic male insulin-dependent diabetics (IDD) following dietary supplementation with either the fish oil concentrate Max EPA or olive oil. The contribution of the small quantity of cholesterol in Max EPA to these changes was also examined. Twenty-seven subjects were matched in groups of three and randomly allocated to one of three treatment groups of nine subjects each. Subjects were given 15 1-g capsules of oil daily for 3 weeks, consisting of either Max EPA, olive oil, or olive oil to which was added the same amount of cholesterol as contained in Max EPA, respectively. There was a significant increase in eicosapentaenoic acid, and a decrease in arachidonic acid, in the platelet membrane phospholipids of subjects taking Max EPA. In this group, there was an approximately 30% increase in serum HDL2-cholesterol (0.59 +/- 0.07 to 0.77 +/- 0.11 mmol/L, mean +/- SEM; P less than .01) and a corresponding decrease in HDL3-cholesterol (0.79 +/- 0.03 to 0.71 +/- 0.03 mmol/L; P less than .05). Although total and LDL-cholesterol concentrations were also higher after Max EPA, the changes were not significant. Triglycerides were significantly decreased by Max EPA. There were no significant changes in lipids in the groups given olive oil. These results show that compared with olive oil, dietary supplementation with Max EPA substantially increases HDL2-cholesterol in insulin-dependent diabetics. This is most likely due to a selective effect of omega 3 fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Fish oil-induced changes in apolipoproteins in IDDM subjects.

The aim of this study was to examine the effect of Max EPA (a commercially available fish oil preparation) on serum cholesterol lipoproteins and apolipoproteins in insulin-dependent diabetic (IDDM) men with dosages that were likely to be acceptable to patients. Twenty-two male IDDM patients aged 20-41 yr, 6 of whom had retinopathy, were recruited from the Royal Perth Hospital diabetic clinic. After screening, subjects were divided into three groups. Six of the subjects without retinopathy were randomly selected and allocated to a control group. The remaining 16 patients (10 without and 6 with retinopathy) received a fish oil supplement. All subjects were advised to maintain their usual dietary patterns. Sixteen patients, including the 6 with retinopathy, were instructed to take 15 Max EPA fish oil capsules/day with meals. Patients in the control group did not take Max EPA. Three weeks of Max EPA supplementation without other dietary modification led to a significant rise in total cholesterol (P less than 0.01), which could be accounted for by increases in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. The increase in HDL cholesterol was explained by a 33% rise (P less than 0.001) in its HDL2 subclass. Changes in apolipoproteins were examined and showed that the level of apolipoprotein A-I increased after ingestion of fish oil and correlated significantly (P less than 0.05) with the rise in HDL cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Controlled comparison of effects of exercise and alcohol on blood pressure and serum high density lipoprotein cholesterol in sedentary males.

1. Seventy-two sedentary male drinkers, aged 20-45 years, and with mean blood pressure (BP) at entry of 132 +/- 1.2/73 +/- 0.9 mmHg, completed a 4 week study during which they were assigned randomly to either drink a low alcohol beer (effectively reducing their weekly alcohol intake from 481 +/- 47 mL to 52 +/- 5 mL) or to continue their normal drinking habits. 2. Within these two groups subjects were further assigned to either a moderate exercise programme of three 30 min sessions per week of stationary cycling at 60-70% maximum workload or to a control light exercise programme where they pedalled against zero or minimal resistance. 3. Both alcohol restriction and moderate exercise were associated with mean falls in bodyweight of 0.5 kg. After adjustment for bodyweight a significant main effect of alcohol restriction on systolic BP (-4.1 +/- 1.7 mmHg, P less than 0.05) and diastolic BP (-1.6 +/- 0.8 mmHg, P = 0.05) was demonstrated. There was no significant main effect of moderate exercise on systolic or diastolic blood pressure despite a significant improvement in physical fitness (maximal oxygen uptake increasing from 33.2 +/- 0.8 mL/kg per min to 35.5 +/- 0.1 mL/kg per min). 4. Significant falls in high density lipoprotein cholesterol (HDLC) and triglyceride levels seen with alcohol restriction were unaffected by the increase in fitness, the magnitude of the fall being similar in both the moderate and light exercise groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary fish oils increase serum lipids in insulin-dependent diabetics compared with healthy controls.

The effect of daily dietary supplementation with fish oil on serum lipids and platelet total phospholipid fatty acids was examined in male normolipidemic insulin-dependent diabetics and normal controls. They were given 15 g/d of fish oil as Max EPA (equivalent to 2.7 g/d of eicosapentaenoic acid) for 3 weeks. The diabetics showed a rise in total cholesterol, attributable to increases in LDL- and HDL-cholesterol. The increase in HDL-cholesterol was largely due to a rise in its HDL2 subclass. There was also a decrease in triglycerides in both groups. Similar changes in lipids were seen in the normal controls, although these were not significant. The more pronounced effect in diabetics suggests an altered metabolic response to omega-3 fatty acids in that disorder. However, the results indicate that the possible detrimental effect of the rise in total and LDL-cholesterol following fish oil may be offset by the increase in the protective HDL2 subclass.

Pseudohyponatraemia, hypercholesterolaemia, and primary biliary cirrhosis.

A 62 year old woman with primary biliary cirrhosis was found to have a plasma sodium concentration of 115 mmol/l. Follow up showed this to be a "pseudohyponatraemia" due to a massively raised serum cholesterol concentration of 78 mmol/l. Electrophoresis of serum lipoproteins and of the lipoproteins and apolipoproteins in fractions isolated on density-gradient ultracentrifugation showed that the major portion of the serum cholesterol was being transported with lipoprotein-X. Low density lipoprotein-cholesterol concentration was also raised. Lipoprotein-X contained, in addition to albumin and apolipoprotein C, apolipoprotein E. This case is of interest because of the degree of hypercholesterolaemia, its association with pseudohyponatraemia, and the unequivocal demonstration of apolipoprotein E associated with lipoprotein-X.

Apolipoprotein A-I and A-II levels in an Australian population.

Values for apolipoproteins A-I and A-II (apo A-I and apo A-II) are reported for 389 women and 390 men in the town of Busselton, Western Australia. Apo A-I levels were found to be relatively constant with age in men but to rise with age in women. Apo A-II levels remained constant with age in men until older age, when they declined, but rose with age in women, showing a fall in the oldest age group. Apo A-I levels were greater in women than in men, but apo A-II levels were lower in younger women than in younger men, and higher in older women than in older men. On stepwise multiple regression analysis, neither apo A-I nor apo A-II levels showed an independent relationship with age in women; the same was true for apo A-I in men. Alcohol consumption was directly associated with apo A-I and A-II levels in both sexes; adiposity was inversely associated with apo A-I levels in both sexes but with apo A-II only in women. Triglyceride levels showed an inverse association with apo A-II in women. Frequency of exercise was independently and directly associated with apo A-I and A-II levels in women only.

Levels of serum cholesterol, triglyceride, HDL-cholesterol, apoproteins A-I and B, and plasma glucose, and prevalence of diastolic hypertension and cigarette smoking in Papua New Guinea highlanders.

Coronary heart disease (CHD) is rare in Papua New Guinea (PNG) highlanders. Fifty-two men and 69 women randomly selected from three rural communities and a low socioeconomic urban community in the Eastern Highlands Province were assessed for hyperlipidemia, diabetes mellitus, diastolic hypertension and cigarette smoking. There was no significant difference between the findings in the rural and urban groups. The mean fasting levels of serum cholesterol, HDL cholesterol and apoproteins A-I and B were significantly lower (p less than 0.001) than those of rural Australians in a comparative study but the serum triglyceride levels were significantly higher in men less than 30 yr and women less than 40 yr of age. There was no significant difference in the serum cholesterol levels in men and women, and the levels of serum cholesterol and triglyceride did not rise with age. The mean fasting levels of plasma glucose were generally lower in PNG subjects and only two (1.7%) had diabetes mellitus. The proportions of highlanders who had diastolic hypertension or who smoked cigarettes were similar to those of Australian populations generally. The low incidence of CHD in PNG highlanders is probably related to the low serum cholesterol and apoprotein B levels, in turn probably related to their basically vegetarian diet and physically active life-style.