Atypical type III hyperlipoproteinemia in a patient with Ig A myelomatosis

Summary We studied a 58-year-old woman with severe therapy-refractory hyperlipidemia, xanthomatosis, and multiple myeloma (immunoglobulin A, lambda light chain). The lipid disorder became evident about half a year prior to the expression of myelomatosis. Clinical symptoms were similar to those found in classical type III hyperlipoproteinemia but the underlying metabolic defect was different from the one described in this primary dyslipoproteinemia. The patient has the heterozygous apolipoprotein E3/2 phenotype and her VLDL-cholesterol/serum-triglyceride ratio is unusually low at 0.05. Evidence is given that the hyperlipoproteinemia is due to an impaired catabolism of intermediate density lipoproteins probably because of a reduced hepatic triglyceride lipase activity.Abbreviations AIH autoimmune hyperlipidemia - Chol cholesterol - HDL high density lipoproteins - HLP hyperlipoproteinemia - HTGL hepatic triglyceride lipase - IDL intermediate density lipoproteins - IEF isoelectric focusing - Ig immunoglobulin - LDL low density lipoproteins - LPL lipoprotein lipase - PL phospholipids - TG triglycerides - VLDL very low density lipoproteins     

Effect of pravastatin on metabolic parameters of apolipoprotein B in patients with mixed hyperlipoproteinemia

Summary 3-Hydroxy-3-methylgluratyl coenzyme A reductase inhibitors reduce plasma cholesterol in different forms of hyperlipoproteinemia. Although an increase in low-density lipoprotein (LDL) receptor activity is the proven mechanism of this therapy in familial hypercholesterolemia, the mechanism remains controversial in mixed hyperlipoproteinemia. A decreased production of apolipoprotein B (apoB) and/or an increased removal of lipoproteins could mediate the hypocholesterolemic effect of these drugs. The effect of pravastatin on the metabolism of apoB was evaluated in a randomized, double blind, placebo controlled, cross-over study in five men with mixed hyperlipoproteinemia. Metabolic parameters for apoB were determined using endogenous labeling with [1^t3C]leucine and [¹⁵N]glycine and multicompartmental modeling. During pravastatin therapy cholesterol, LDL cholesterol, apoB, and LDL apoB levels were significantly reduced (P < 0.01) by 18%, 20%, 27%, and 29%, respectively, while triglyceride and high-density lipoprotein cholesterol levels remained unchanged. Pravastatin therapy increased the fractional catabolic rate of very low density lipoprotein apoB from 3.9±0.6 to 5.1±1.7 per day (P = 0.08) and that of LDL apoB from 0.37±0.09 to 0.46±0.10 per day (P<0.01). The apoB production (placebo 35.2±11.9 mg/kg per day; pravastatin 25.8±8.7 mg/kg per day) and conversion of very low density lipoprotein apoB to LDL apoB (placebo 65%, pravastatin 57%) remained stable. Thus, also in mixed hyperlipoproteinemia 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase the catabolism of apoB-containing lipoproteins without significantly affecting the production of apoB.Abbreviations apoB apolipoprotein B - FCR fractional catabolic rate - HMG hydroxy-methylglutaryl - CoA coenzyme A - FH familial hypercholesterolemia - HDL high-density lipoprotein - IDL intermediate-density lipoprotein - LDL low-density lipoprotein - VLDL very low density lipoprotein Dedicated to Prof. Dr. G. Paumgartner on the occasion of his 60th birthday     

The influence of simvastatin alone or in combination with gemfibrozil on plasma lipids and lipoproteins in patients with type III hyperlipoproteinemia

Summary Nineteen adult patients with type III hyperlipoproteinemia (HLP) and homozygosity for apolipoprotein (apo) E2 were treated with the 3-hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase inhibitor simvastatin (20 or 40 mg per day) alone or in combination with the fibrate derivative gemfibrozil (450 mg per day) during a 30-week outpatient study. With the 20-mg dose (n = 19) the mean plasma cholesterol level decreased from 13.24±8.04 8.04 at baseline to 8.04±4.19 mmol/l (mean reduction 39.3%; P<0.05), and the mean plasma triglyceride level decreased from 13.47±19.22 to 7.84±7.71 mmol/l (–41.8%; NS); this was due to a decrease in very low density lipoprotein (VLDL) cholesterol from 8.95±8.64 to 4.94±4.24mmo1/l (–44.8%; NS), a decrease in low density lipoprotein (LDL) cholesterol from 3.54±0.93to 2.25 ± 0.59 mmol/l (–36.5%; P<0.01), and an increase in high density lipoprotein (HDL) cholesterol from 0.72±0.28 to 0.85±0.34 (+18.1%; NS). Thirteen patients were treated with 40 mg simvastatin per day. Under this regimen there was a further significant decrease in LDL cholesterol from 2.33±0.62 to 1.81±0.49 mmol/l (–22.3%; P<0.01). In six patients who remained hyperlipidemic on monotherapy combination drug therapy with simvastatin (40 mg per day) and gemfibrozil (450 mg per day) was given. Compared to simvastatin alone the addition of gemfibrozil further lowered plasma concentrations of total cholesterol by 14.9%, VLDL cholesterol by 23.5%, and triglycerides by 17.1%, although this was not statistically significant. No patient was discontinued from single or combination drug therapy, and no severe clinical or biochemical side effects were observed. The results of this study demonstrate the usefulness of simvastatin in the therapy of type III HLP and indicate that in individual patients who remain hyperlipidemic on monotherapy combination drug therapy with both of these drugs is effective in further reducing plasma concentrations of total cholesterol, VLDL cholesterol, and triglycerides. Although no patient in this investigation developed myopathy or rhabdomyolysis, combined fibrate-HMG CoA reductase inhibitor treatment should be considered only for severe forms of hyperlipidemia and for patients who do not respond sufficiently to mon-therapy of any of these drugs.Abbreviations Apo Apolipoprotein - CPK creatine phosphokinase - GGT gamma-glutamyl transpeptidase - HDL high density lipoproteins - HLP hyperlipoproteinemia - HMG CoA 3-hydroxy-3-methyl glutaryl coenzyme A - IDL intermediate density lipoproteins - LDL low density lipoproteins - TG triglycerides - VLDL very low density lipoproteins     

Lipoprotein pattern in long-term diabetes of an at least 35 years' duration

Summary All diabetic patients suffering from the disease for at least 20 years and living in the closed area of the Erfurt district in 1970 have been followed prospectively since that time. In 47 of them still alive in 1985, i.e. after more than 35 years of diabetes, serum lipid and apolipoprotein concentrations were measured and compared to those of non-diabetic subjects without cardiovascular diseases (n=47) pair-matched by sex, age, and body weight. In males (n=27) significantly (p<0.01) higher levels of HDL cholesterol and apolipoprotein A–I as well as lower concentrations of triglycerides and a lower total cholesterol/HDL cholesterol risk ratio than in nondiabetic control subjects could be found. In long-term diabetic females (n=20), apolipoprotein A–I levels were also increased (p<0.02). Trends in HDL cholesterol and triglycerides were similar to those found in males but did not reach statistical significance. Higher concentrations of total cholesterol (p<0.02), LDL cholesterol (P<0.05), and apolipoprotein B (p<0.02), however, did not fit in with a beneficial lipoprotein pattern. The frequency of pathological lipoprotein patterns was not higher than among the non-diabetic control subjects (32% and 40%, respectively). According to these findings an antiatherogenic lipoprotein pattern might be considered, at least in males, as one of the determinants causing the multifactorial event of long-term survival in diabetes.Abbreviations ECG electrocardiogramm - Hb haemoglobin - HDL high density lipoproteins - LDL low density lipoproteins - SD standard deviation - VLDL very low density lipoproteins     

Response to therapy of a type III hyperlipoproteinemic subject with the rare apolipoprotein E1 (Gly127 → Asp,Arg158 → Cys) variant

Summary In a preceding paper, we described the molecular biological defects in a patient with a severe form of the familial lipoprotein disorder type III hyperlipoproteinemia (HLP) and an unusual apolipoprotein (apo) El phenotype and 1/null genotype. The index case was a 60-year-old white male of German ancestry who suffered from a myocardial infarction at age 50 years. He had distinctly elevated levels of plasma lipids (triglycerides 551 mg/dl and cholesterol 747 mg/dl, respectively) and typical clinical signs of this inborn error of lipoprotein metabolism. His mutant apo E1 was shown to be identical to a rare (already described) apo E1 (Gly₁₂₇Asp, Arg₁₅₈Cys) variant. A second independent defect at the molecular level was a nucleotide deletion of a guanosine (G) in the codon for amino acid 31 of the proband's apo 3 allele. This single base deletion (not described before) changed his apo 3 allele to a nonfunctional null allele devoid of a stable gene product. Here we describe the response to combined dietary and medical treatment of the patient with this unusual form of type III HLP. His response to therapy was excellent, similar to patients with classical type III HLP and homozygosity for apo E2. However, the correct diagnosis of this familial lipoprotein disorder seems to be necessary, even in patients without the expected apo E2/2 phenotype, in terms of the prompt and beneficial response to therapeutic interventions.Abbreviations Apo Apolipoprotein - Chol cholesterol - HDL high density lipoproteins - HDL-C HDL-cholesterol - HLP hyperlipoproteinemia - IDL intermediate density lipoproteins - IEF isoelectric focusing - LDL low density lipoproteins - LDL-C LDL-cholesterol - TG triglycerides - VLDL very low density lipoproteins - VLDL-C VLDL-cholesterol Dedicated to Prof. Dr. G. Schettler on the occasion of his 75th birthday on April 13, 1992     

Fenofibrate improves postprandial chylomicron clearance in II B hyperlipoproteinemia

In 11 patients with 1113 hyperlipoproteinemia we studied fasting lipids, lipoproteins, lipoprotein-modifying enzymes, and postprandial lipid metabolism after a standardized oral fat load supplemented with vitamin A before and 12 weeks after treatment with fenofibrate, a third-generation fibric acid derivative. Fasting plasma cholesterol, triglycerides, low-density lipoprotein cholesterol decreased significantly (P < 0.05, P < 0.01, P < 0.01), high-density lipoprotein subfraction 3 cholesterol increased significantly (P < 0.05), and high-density lipoprotein subfraction 2 cholesterol remained unchanged. Postprandial lipemia, i.e., the integrated postprandial triglyceride concentrations corrected for the fasting triglyceride level, and postprandial chylomicron concentrations, as assessed by biosynthetic labeling of chylomicrons with retinyl palmitate, decreased by 40.6% and 60.1% (P < 0.05; P < 0.05), respectively. The activity of lipoprotein lipase (LPL) increased by 33.6% (P < 0.05); the increase in LPL during fenofibrate treatment was positively correlated with the increase in high-density lipoprotein cholesterol (r = 0.84; P < 0.005). Hepatic lipase and cholesteryl ester transfer protein mass and activity remained unchanged. We conclude that lipid-lowering therapy with fenofibrate ameliorates fasting and, more profoundly, postprandial lipoprotein transport in hypertriglyceridemia by curbing postprandial triglyceride and chylomicron accumulation, at least in part, through an increase in LPL activity.Abbreviations LDL low-density lipoproteins - HDL high-density lipoproteins - LPL lipoprotein lipase - HL hepatic lipase - CETP cholesteryl ester transfer protein - CHD coronary heart disease - VLDL very low density lipoproteins - TG triglycerides - apo apolipoprotein Correspondence to: J.R. Patsch     

Evaluation of the classical methods for the diagnosis of type III hyperlipoproteinemia

Summary Familial type III hyperlipoproteinemia is characterized by the presence of elevated plasma levels of very low density lipoproteins (VLDL) which contain an increased amount of cholesterol and by the presence of a significant amount of lipoproteins with an intermediate density between that of VLDL and low density lipoproteins (LDL); the intermediate density lipoproteins, designated IDL or Lp III, have a slower electrophoretic migration rate than VLDL, and are found in the ultracentrifugal top fraction as a contaminant. Classically, the diagnosis of type III is based on the demonstration of beta-migrating lipoproteins in the ultracentrifugal top fraction (density <1.006), thus floating beta-lipoprotein. More recently, it has been proposed that an elevated VLDL-cholesterol to triglyceride ratio is diagnostic of the disorder. In the present report, we have compared the two methods for their diagnostic value and have concluded that the chemical index definition is the more reliable method for the diagnosis of type III hyperlipoproteinemia.     

Treatment of patients with familial defective apolipoprotein B-100 with pravastatin and gemfibrozil: a two-period cross-over study

Thirty patients with familial defective apolipoprotein B-100 were treated in a two-period (8 weeks each) cross-over study with pravastatin and gemfibrozil. Cholesterol, LDL cholesterol, and apo B were reduced by 20–25% (P < 10^–4) by pravastatin and by 4–6% by gemfibrozil (pravastatin vs. gemfibrozil:P < 10^–4). Response to pravastatin was variable and not correlated to gender, age, or apo E genotype. Gemfibrozil lowered triglycerides by 25% (P < 10^–4) and raised HDL cholesterol by 11%. The effects of pravastatin on these two interrelated variables were significantly smaller. Both drugs increased Lp(a) significantly by about 10%. The LDL cholesterol lowering effect of pravastatin in patients with FDB is similar to that observed in patients with familial hypercholesterolemia.Abbreviations FDB familial defective apolipoprotein B-100 - LDL low density lipoprotein - VLDL very low density lipoprotein - HDL high density lipoprotein - LDL-R low density lipoprotein receptor - HMG CoA -hydroxy--methyl-glutaryl coenzyme A - FH familial hypercholesterolemia - TG triglycerides - apo B apolipoprotein B-100 - apo Al apolipoprotein Al - apo E apolipoprotein E - Lp(a) lipoprotein(a) - PCR polymerase chain reaction Correspondence to: P.S. Hansen     

Treatment of coronary heart disease by diet and exercise: Fasting and diurnal lipoproteins

Summary The effects of a combined exercise and low-fat dientary regimen were studied in 11 patients with angiographically documented coronary heart disease (cholesterol 233 mg/dl, triglycerides 158 mg/dl) and 13 comparable patients (cholesterol 224 mg/dl, triglycerides 174 mg/dl) on usual care. During one year, fasting serum lipoproteins were lowered to ideal levels in the intervention group (cholesterol 191 mg/dl, triglycerides 100 mg/dl, LDL-cholesterol 121 mg/dl). There was no change of triglycerides and cholesterol on usual care while LDL-cholesterol rose significantly. Neither regimen had any effect on HDL-cholesterol. Diurnal triglycerides as a presumptive measure of IDL in the intervention group were diminished by 39%. The study demonstrates the feasibility of a diet and exercise regimen to normalize midly elevated plasma lipid levels and thus to possibly affect the course of coronary heart disease without drugs.Abbreviations Chol cholesterol - TG triglycerides - HDL high density lipoproteins - LDL low density lipoproteins - LP(a) lipoprotein (a) - P/S polyunsaturated to saturated fatty acid ratio - Int. Intervention group - C Control group Supported by Bundesministerium für Forschung und Technologie     

Effects of fish oil concentrate on lipoproteins and apolipoproteins in familial combined hyperlipidemia

Summary The effects of two moderate doses of long-chain n-3 fatty acids (3.0 and 4.5 g EPA + DHA per day for 4 weeks each) on serum lipids and lipoproteins of patients with familial combined hyperlipidemia (FCH) were studied in a double-blind, placebo-controlled clinical trial. In nine patients with FCH n-3 fatty acids led to a statistically significant, dose-dependent fall in very low density lipoprotein (VLDL) triglycerides (3 g/day: –42%, 4.5 g/day: –55%) VLDL cholesterol (3 g/day: –41%, 4.5 g/day: –47%), and VLDL apolipoprotein (apo) B-100 (3 g/day: –40%, 4.5 g/day: –56%). No overall change in low-density lipoprotein (LDL) cholesterol was found, as confirmed statistically. However, when analyzing the data of single patients LDL cholesterol and LDL apo B did not change in five patients but increased dose dependently (from pretreatment 4.80±0.93 mmol/l to 5.70+0.93 mmol/l LDL cholesterol after 4.5 g/day) in four. LDL and VLDL composition as indicated by cholesterol/apo B-100 and triglyceride/apo B-100 ratios did not change significantly. High-density lipoprotein (HDL) cholesterol was unchanged; the HDL cholesterol/apo A-I+apo A-II ratio increased by 19% (P<0.05) during fish oil treatment. We conclude that in FCH moderate doses of long-chain n-3 fatty acids are highly effective in lowering pathological VLDL triglycerides, VLDL cholesterol, and VLDL apo B. LDL cholesterol must, however, be monitored during treatment as it may rise substantially in some although not in all patients with this disease.Abbreviations EPA eicosapentaenoic acid - DHA docosahexaenoic acid - FCH familial combined hyperlipidemia - VLDL very low density lipoprotein - LDL low-density lipoprotein - HDL high-density lipoprotein - apo apolipoprotein Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday     

Abfall der Serumlipoproteine und Anstieg der Apolipoproteine A-I und A-II nach oraler Zufuhr mehrfach ungesättigter Phospholipide

Summary Polyenylphosphatidylcholine was given orally in a dosage of 10 g per day to 10 healthy subjects for 4 weeks. The concentrations of cholesterol, triglycerides, phospholipids, apolipoproteins AI, AII, and B were measured in serum, as were very low density lipoproteins, low density lipoproteins, and high density lipoproteins every 3 h on the day before and after the 4 weeks of application. The diet was controlled 10 days before and during the experiment using the dietary recall method. The evaluation of the diet records showed that 5 subjects had increased and 5 subjects had decreased their fat consumption in exchange for carbohydrates during the experiment. Nevertheless body weight remained constant within ±1 kg. Cholesterol in serum and low density lipoprotein decreased, but the differences were not statistically significant. In spite of dietary changes apolipoprotein AI and AII in high density lipoproteins increased significantly. We conclude that the influence of drugs on serum lipids can only be evaluated in conjunction with reliable control of the diet.

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Abkürzungen PPC Polyenylphosphatidylcholin - VLDL Very low density lipoproteins - LDL Low density lipoproteins - HDL High density lipoproteins - LCAT Lecithin-Cholesterin-Acyl-Transferase     

Lipid changes in the nephrotic syndrome: New insights into pathomechanisms and treatment

Summary The abnormalities of lipid metabolism in nephrotic syndrome consist in an increase in total and low-density lipoprotein (LDL) cholesterol, apoliproteins B (ApoB), C-II and C-III, associated in patients with heavier or marked hypoalbuminemia with an increase in triglycerides and very low-density lipoprotein (VLDL) cholesterol, while the high-density lipoproteins (HDL) are distributed abnormally (increased HDL3 fraction and decreased HDL2 fraction) and the Apo A-I to Apo B ratio is reduced. Both increased hepatic lipoprotein synthesis and reduced removal capacity contribute to this hyperlipidemia. Proteinuria may lead to the lipoprotein abnormalities through stimulation of VLDL synthesis by the liver induced by hypoalbuminemia, although it has been more recently suggested that urinary protein loss is associated with the urinary loss of some important cofactor for the regulation of lipid synthesis or catabolism.Treatment of lipid abnormalities in patients with long-lasting heavy proteinuria is mandatory, because they may cause or contribute to accelerated atherosclerosis, but also because they appear to accelerate progression of renal disease by favouring mesangial sclerosis. Four groups of lipidlowering drugs have been tested: 1) bile acid-binding resins; 2) fibric acid; 3) probucol; 4) inhibitors of HMG CoA reductase. The drugs of the last group appear to be effective and safe in short-term experiments, but long-term studies are necessary to confirm their validity. A dietary approach, consisting in a strictly vegetarian soy diet, very rich in polyand monounsaturates fatty acids, has been recently tested by the author, with very promising results.Abbreviations LDL low density lipoproteins - VLDL very low density lipoproteins - HDL high density lipoproteins - Apo Apolipoprotein - LCAT Lecithin cholesterol acyltransferase - HMGCoA Hydroxymethylglutaryl coenzyme A Preprint of a lecture to be read at the 22nd Congress of the Gesellschaft für Nephrologie, Heidelberg, September 15–18, 1991 (Editor: Prof. Dr. E. Ritz, Heidelberg)     

Changes of serum lipid patterns during long-term anticonvulsive treatment

Summary Serum lipids were determined in 97 patients (56 men, 41 women; ages 42±15 years) undergoing long-term anticonvulsive treatment (longer than 6 months). The total group showed increased total cholesterol, decreased high-density lipoprotein HDL cholesterol, an increased ratio of total to HDL cholesterol, and decreased apolipoprotein A1 and B values compared to population means. Considering males and females separately, all differences were significant (P<0.01) in men, whereas in women only the differences in HDL cholesterol, ratio of total to HDL cholesterol, and apolipoproteins A1 and B reached the level of statistical significance. Considering the different anticonvulsant groups, cholesterol was significantly increased only in phenytoin-treated males; HDL cholesterol was significantly lowered and the ratio of total to HDL cholesterol significantly increased in all groups. Apolipoprotein A1 levels were significantly decreased in phenytoin-treated females and valproate-treated patients of both sexes. Apolipoprotein B levels were significantly decreased in all groups except carbamazepine-treated males. Especially in men treated with anticonvulsants these lipid levels may be considered a risk factor for atherosclerosis.Abbreviations -GT gamma-glutamyltransaminase - GOT glutamic oxaloacetic transaminase - GPT glutamic pyruvic transaminase - HDL high-density lipoprotein - LDL low-density lipoprotein     

Unusual xanthomas in a young patient with heterozygous familial hypercholesterolemia and type III hyperlipoproteinemia

We report on a 20-year-old man with the combination of two independent familial lipoprotein disorders: heterozygous familial hypercholesterolemia (FH) and type III hyperlipoproteinemia (HLP). Familial hypercholesterolemia was diagnosed by elevated total and low density lipoprotein cholesterol levels and family history. By denaturing gradient gel electrophoresis, DNA sequencing and restriction fragment length polymorphism analysis, a G→A splice donor mutation in intron 3 of the proband's low density lipoprotein receptor gene was identified as the underlying molecular defect. This mutation was described previously as a receptor-negative founder mutation in Norway (FH-Elverum) and subsequently in 6 unrelated heterozygous English patients, creating a severe phenotype of familial hypercholesterolemia. Type III HLP was confirmed by homozygosity for apolipoprotein (apo) E2 and an elevated ratio of very low density lipoprotein cholesterol to serum triglycerides (0.40; normal ratio about 0.20). The patient has unusual flat xanthomas in the interdigital webs of the hands which are normally not found in either disease. These dermatological findings might therefore be indicative of the rare combination of both disorders of lipoprotein metabolism in one individual. © 1996 Wiley-Liss, Inc.     

Methods of biochemical analysis in hyperliproproteinemias

In the past years, the structure and function of the plasma lipoproteins and apolipoproteins have been elucidated. The biochemical defect of several genetic lipoprotein disorders and their role in the development of atherosclerosis are now well understood. Electrophoretic separation of lipoproteins in polyacrylamide gradient gel gives an acurate characterization of the different lipoproteins and allows the phenotyping of hyperlipoproteinemia. Abnormal concentrations of plasma lipoproteins have been known for many years to be a major risk factor in the development of premature ischemic heart disease. Although large-scale epidemiological studies have focused attention on the association between above-normal concentrations of plasma lipids and coronary atherosclerosis, recent findings have shown that quantitative lipoprotein and apoprotein determination may be a more nearly accurate predictor in the recognition of atherosclerosis. The risk for vascular disease seems to be particularly associated with an increase in the concentrations of apolipoprotein B (apo B), the major protein moiety of low density lipoproteins and a decrease in apolipoprotein Al, the major polypeptide of high-density lipoproteins.     

The effect of the apolipoprotein E polymorphism on lipid levels in patients with familial defective apolipoprotein B-100

Summary Serum lipid concentrations of patients with familial defective apolipoprotein B-100 (FDB) show a high interindividual variability although the underlying defect is caused by a single point mutation. On the other hand, several genetic factors modulating serum cholesterol levels are known, such as DNA polymorphisms of the apopolipoprotein B or the apolipoprotein E (apo E) gene. To assess the effect of the apo E polymorphism on serum cholesterol, lipid levels of FDB patients (n=36) were compared with those of a normolipidemic control group (n=272) according to their apo E genotype. For the FDB group mean values of low-density lipoprotein (LDL) cholesterol (mg/dl) were 225.7 ± 53.7 for E3/2 genotype (n = 3), 234.2±48.3 for E3/3 genotype (n=20), and 252.4±73.8 for E4/3 genotype (n=13). Means of triglycerides (mg/dl) were 121.0±21.2, 114.8± 60.7, and 110.0 ± 62.8 for the respective apo E genotypes. The calculated average effect of the apo E alleles on LDL cholesterol levels was –6.0% for allele e2 and +3.7% for e4 relative to the whole FDB group. The effect on triglyceride levels was +7.5% for e2 and –3.6% for e4. The control group showed a similar variation in LDL cholesterol depending on the different apo E genotypes. About 6% of the total variation in LDL cholesterol can be accounted for by the apo E locus in normolipidemic and hypercholesterolemic individuals alike.Abbreviations FDB familial defective apolipoprotein B-100 - apo apolipoprotein - LDL low-density lipoprotein - VLDL very low density lipoprotein - HDL high-density lipoprotein - PCR polymerase chain reaction Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday     

Altered lipoprotein composition and elevated serum lipids in chicken embryos with hereditary muscular dystrophy

The earliest biochemical changes reported in chickens with hereditary muscular dystrophy are increased cholesterol levels in liver, serum and pectoral muscles at 9 days of embryonic development. We have investigated whether there were concomitant differences in serum lipoprotein composition (VLDL, very low density lipoproteins; LDL, low density lipoproteins; HDL high density lipoproteins)**, and levels of serum triglycerides (TG), free cholesterol (FC) and cholesteryl esters (CE) in normal chicken embryos and in those with hereditary muscular dystrophy between 10 and 16 days in ovo. VLDL and CE content of the serum of dystrophic embryos are significantly elevated compared to those of the normal serum from 10 to 16 days in ovo, and serum TG is significantly increased at 12 and 14 days in ovo. Serum LDL and HDL concentrations are significantly lower in dystrophic embryos at 14, 16 and 12 days respectively. It is proposed that an increased rate of CE synthesis, probably in the liver, induces the formation of CE-rich, TG-poor VDLD-like lipoprotein. Decreased degradation of this lipoprotein by peripheral tissues, especially muscles, may account for the high VLDL levels in the dystrophic embryos. Since dystrophic chickens exhibit hyperlipoproteinemia followed by muscle degeneration, this disease has features in common with human spinal muscular atrophy.     

Familial hyperlipoproteinemia and thyroid dysfunction of beagles

Some biological characteristics of beagle dogs with familial hyperlipoproteinemia were reported. Data were obtained from hyperlipoproteinemic beagles and from normolipoproteinemic beagles of a similar age range (4 to 8 yr) and normolipoproteinemic beagles 1 to 2.5 yr of age. Affected dogs were markedly hyperlipoproteinemic even though the diet contained less than 8% fat and less than 0.05% cholesterol. Serum total lipid concentrations were 3-fold higher in affected beagles; the greatest percentage increase was in triglycerides and cholesterol which averaged 986 and 627 mg/dl, respectively. Normolipoproteinemic dogs had essentially no low density (LD) or very low density (VLD) lipoprotein as determined by electrophoresis in agarose gel, whereas LD and VLD lipoproteins predominated in hyperlipoproteinemic beagles. Hyperlipoproteinemic dogs had mildly impaired carbohydrate tolerance and relative hyperinsulinemia during intravenous glucose tolerance tests. Primary hypothyroidism was considered the major cause of hyperlipoproteinemia because affected dogs had significantly lower concentrations of serum thyroxin (T₄) and essentially no change in the levels of serum T₄ after injection of thyrotropin. Additionally, data obtained from in vitro triiodothyronine uptake tests revealed relative unsaturation of serum thyroxine binding protein in dogs with hyperlipoproteinemia.     

Lipoprotein lipase activity in patients with combined hyperlipidaemia

The aetiology of familial combined hyperlipidaemia remains obscure, with both genetic and environmental factors contributing to the phenotype, which is frequently associated with premature coronary heart disease. We have studied lipoprotein lipase (LPL) activity and hepatic lipase (HL) activity in patients with coronary heart disease to determine whether variation in lipase activities contributes to this phenotype. Forty-one patients (mean age 50 years; 30 male) were selected on the basis of cholesterol levels above 6.5 mmol/l and triglyceride levels above 2.2 mmol/1, with apoprotein B values over the 90th percentile. There was a family history of premature coronary heart disease in 78% and a personal history in 64%, at mean age 44, the patient group therefore predominantly corresponded to the common definition of familial combined hyperlipidaemia, appropriate in the absence of molecular markers. None of the patients was diabetic; hypertension and smoking were not over represented. Blood samples were taken following intravenous administration of heparin (100IU/kg body wt), and LPL and HL activities were measured. Mean post-heparin LPL was significantly lower in patients than controls 10 min after heparin administration (2.98 ± 1.04 and 3.86 ± 0.93 mol ml^-1 h^-1, respectively, P = 0.001), and 37% patients had values below the 10th percentile of controls. Both male and female patients had significantly higher HL activities than their respective controls at 5, 10, 20 and 30 minutes postheparin. As expected, both female patients and controls had lower HL activities than males, although this sex difference did not reach statistical significance in the patient group. Mean lipid and lipoprotein results were: cholesterol 8.2 mmol/1; triglycerides 4.2 mmol/l; high-density lipoprotein cholesterol 0.90 mmol/1; apoprotein Al 122 mg/dl; apoprotein B 171 mg/dl; lipoprotein (a) 23 mg/dl (median 10 mg/dl). High-density lipoprotein cholesterol and triglycerides were negatively correlated (r = -0.26, P = 0.05). HL was significantly related to body mass index at all time points whereas the negative correlation between post-heparin LPL and body mass index was significant only 30 min after heparin administration. Post-heparin LPL was only weakly correlated with triglycerides 10 and 20 min after heparin administration. These lipid and lipoprotein results are clearly potentially atherogenic as indicated by the extent of premature coronary heart disease in the group described. A decrease in LPL activity may contribute to this pattern.Abbreviations FCHL familial combined hyperlipidaemia - CHD coronary heart disease - LPL lipoprotein lipase - HL hepatic lipase - HDL high-density lipoprotein - VLDL very low density lipoprotein; - apo apoprotein - TG triglyceride - BMI body mass index Correspondence to: M. Seed     

Effects of long-term treatment with simvastatin on plasma lipids and lipoproteins in patients with primary hypercholesterolemia

Summary We investigated long-term hypolipidemic effects and clinical safety of simvastatin, a new competitive inhibitor of 3-hydroxy-methylglutaryl coenzyme A reductase in 24 patients with familial and non-familial hypercholesterolemia. Patients received up to 40 mg simvastatin for a period of 30 months. Significant decreases were noted in plasma cholesterol (30%), plasma triglycerides (25%), very low density lipoprotein-cholesterol (26%), and low density lipoprotein-cholesterol (40%), whereas an increase in plasma high density lipoprotein-cholesterol (11%) was observed. Furthermore, the percentage decrease in plasma low density lipoprotein cholesterol was independent of individual baseline concentrations. Simvastatin did not alter the composition of low density lipoproteins or high density lipoproteins. The percentage decrease in total plasma and low density lipoprotein-cholesterol was independent of apoprotein E isoforms and low density lipoprotein-receptor activity as assayed in cultured fibroblasts. The drug therapy was well tolerated and clinical examinations revealed no adverse effects. Clinical chemistry indices and hematological, as well as endocrinological parameters remained within normal limits and ranges.Abbreviations VLDL very low density lipoprotein - LDL low density lipoprotein - HDL high density lipoprotein - CHD coronary heart disease - LDL-C low density lipoprotein-cholesterol - FH familial hypercholesterolemia - HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A - HELP heparin extracorporeal low density lipoprotein precipitation This work was supported by a grant from the Deutsche Forschungsgemeinschaft to A.K. Walli (Wa 458/I-1)Dedicated to Prof. Dr. med. F. Scheler on the occasion of his 65th birthday