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     

Deficiency of hepatic lipase activity in post-heparin plasma in familial hyper-alpha-triglyceridemia

Hyper-alpha-triglyceridemia is a rare dyslipoproteinemia characterized by a pronounced increase in the concentration of triglycerides in the plasma high density lipoprotein (HDL) fraction. One case with this condition, an apparently healthy 61-year-old man, has been studied. Additional lipoprotein abnormalities were present, such as abnormally cholesterol-rich very low density lipoproteins (VLDL) with retarded electrophoretic mobility (beta-VLDL) and triglyceride enrichment of low density lipoproteins (LDL). The patient's plasma concentration of apolipoproteins A-I, A-II and B were normal and those of C-I, C-II, C-III and E were elevated. No abnormal forms of the soluble apolipoproteins of VLDL and high density lipoproteins (HDL) were found after analysis by isoelectric focusing. Lecithin:cholesterol acyltransferase activities, plasma cholesterol esterification rates and lipid transfer protein activities were normal. Post-heparin plasma activity of hepatic lipase was virtually absent and that of lipoprotein lipase was reduced by 50%. In plasma of this patient, HDL was almost exclusively present as large triglyceride-rich particles corresponding in size to particles of the HDL2 density fraction. The only brother of the patient also had hyper-alpha-triglyceridemia together with the other lipoprotein abnormalities described for the index case and deficiency of postheparin plasma activity of hepatic lipase. The findings presented below support the hypothesis that one primary function of hepatic lipase is associated with degradation of plasma HDL2. Deficiency of this enzyme activity thus causes accumulation of HDL2 in plasma leading to hyper-alpha-triglyceridemia. The results further suggest that the abnormal chemical and electrophoretic properties of VLDL and LDL in plasma from the patient, reminiscent of type III hyperlipoproteinemia, are secondary to the lack of the action of hepatic lipase on the HDL particles.     

Distribution of apolipoprotein E isoforms between very low and high density lipoproteins of normal subjects and hyperlipidemic patients with special reference to type III hyperlipidemia

Serum very low (VLDL) and high density lipoproteins (HDL) from 17 hyperlipidemic patients and 10 normal subjects have been isolated by preparative ultracentrifugation, and the electrophoretic patterns of apolipoprotein E (apo E) isoforms in the lipoproteins have been examined by isoelectric focusing. Type III hyperlipidemia (dyslipoproteinemia) has been suggested to be a disease caused by an abnormal mutant of the apo E-3 isoform. In accordance with this, all patients with type III hyperlipidemia in the present study showed lack of apo E-3 in VLDL. However, all these patients demonstrated a protein zone corresponding to apo E-3 in their HDL fraction. Patients with other types of hyperlipidemia or normal subjects who showed an apo E-4 variant in VLDL had an HDL that lacked apo E-4. The results support the hypothesis that type III hyperlipidemia is due to an abnormal composition of the VLDL particles rather than a result of an abnormal mutant of apo E-3.     

Down syndrome with low hypodiploidy in precursor B-cell acute lymphoblastic leukemia

We describe the rare finding of a 33-month-old child neonatally diagnosed with Down syndrome, who presented with pre-B acute lymphoblastic leukemia (ALL) with a pretreatment bone marrow karyotype in which a low hypodiploid cell line (38 chromosomes) was identified in 17/19 cells studied. The abnormal cell line retained the extra constitutional chromosome 21. Hypodiploidy (loss of one or more chromosomes) is seen in approximately 5% of all childhood pre-B ALL cases and in approximately 2.2% cases of individuals with a constitutional trisomy 21. Low hypodiploidy, associated with a high risk of relapse, is rare in pediatric ALL cases in the general population, and, to our knowledge, is previously unreported in patients with trisomy 21.     

Hepatic lipase, high density lipoproteins, and hypertriglyceridemia

Hepatic lipase (HL) is a lipolytic enzyme that contributes to the regulation of plasma triglyceride (TG) levels. Elevated TG levels may increase the risk of developing coronary heart disease, and studies suggest that mutations in the HL gene may be associated with elevated TG levels and increased risk of coronary heart disease. Hepatic lipase facilitates the clearance of TG from the very low density lipoprotein (VLDL) pool, and this function is governed by the composition and quality of high density lipoprotein (HDL) particles. In humans, HL is a liver resident enzyme regulated by factors that release it from the liver and activate it in the bloodstream. HDL regulates the release of HL from the liver and HDL structure controls HL transport and activation in the circulation. Alterations in HDL-apolipoprotein composition can perturb HL function by inhibiting the release and activation of the enzyme. HDL structure may therefore affect plasma TG levels and coronary heart disease risk.     

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     

Metabolic disorders of lipoproteins--influences of compositional changes of lipoproteins upon their metabolic behavior

Compositional changes of apoproteins and lipids in lipoproteins influence their affinities for receptors and enzymes. Decrease of apo C proteins and increase of apo E in chylomicron and very low density lipoproteins (VLDL) during their catabolism might promote the binding to remnant receptor. On the other hand, the affinity for lipoprotein lipase (LPL) gradually decreases and that for hepatic lipase increases. However, the responsiveness of VLDL to LPL might be under the control of triglyceride (TG)/surface component ratios but not of the apoprotein ratios in ordinary circumstances judging from the results of the releases of fatty acids from VLDL by LPL in vitro. Responses of VLDL from diabetic patients to LPL significantly decreased compared with those from non-diabetic subjects. Glycation of VLDL in vitro impaired their responses to LPL. Therefore, delayed catabolism of VLDL in diabetes might partially depend upon glycation of VLDL besides the decreased LPL activity. Low density lipoproteins (LDL), apoproteins of which consist mostly of apo B protein and had a low TG level, showed a high affinity to the LDL receptor. However, LDL from hypertriglyceridemic subjects, in which the TG contents was increased, had a low affinity to the receptor. Since high density lipoproteins (HDL) from patients in acute phases contain a large amount of serum amyloid A protein (SAA), the percentages of apo A proteins markedly decreased. When SAA-rich HDL were incubated with leucocytes, SAA were degraded rapidly, although other apoproteins remained to be unchanged. Therefore, such HDL become unstable, and this might induce low HDL levels in the acute phase.     

Effect of furosemide on the lipid abnormalities in chronic renal failure

The effect of furosemide on the lipoprotein profile and the activities of postherapin plasma lipases were studied in 12 patients with chronic renal failure. The concentrations of serum total, VLDL and LDL triglycerides were significantly higher and the concentration of HDL triglyceride was significantly lower in the patients with renal failure than in healthy controls. HDL cholesterol was significantly lower in the patients than in the controls. The activity of postherapin lipoprotein lipase was significantly lower in the patients than in the controls. The introduction of furosemide induced a significant increase in the concentrations of VLDL cholesterol and VLDL triglyceride. These changes were reversed when the drug treatment was discontinued. Postherapin lipase activities were not further altered by furosemide.     

Selective deficiency of hepatic triglyceride lipase in uremic patients.

To investigate the pathogenesis of hypertriglyceridemia in patients with renal disease we measured plasma lipoprotein composition as well as hepatic triglyceride lipase and lipoprotein lipase in post-heparin plasma. Three groups with renal disease were studied: conservatively treated chronic uremia; patients undergoing maintenance hemodialysis; and renal-allograft recipients. A selective decrease of hepatic triglyceride lipase with normal lipoprotein lipase was found in conservatively treated uremia and in patients undergoing hemodialysis. Elevated levels of very-low-density lipoproteins and increased triglycerides in low-density lipoproteins occurred in these patients. In contrast, hepatic triglyceride lipase and lipoprotein lipase were both normal in patients after renal transplantation who had Type II hyperlipoproteinemia as a common lipoprotein pattern with increased low-density-lipoprotein cholesterol and decreased high-density-lipoprotein cholesterol concentrations. The accumulation of a triglyceride-rich low-density lipoprotein in the majority of patients with renal disease may be the consequence of low hepatic triglyceride lipase.     

The lipoprotein lipase Gly188----Glu mutation in South Africans of Indian descent: evidence suggesting common origins and an increased frequency.

Lipoprotein lipase (LPL) plays a crucial role in the hydrolysis of the triglyceride core of circulating chylomicrons and very low density lipoproteins (VLDL) and also has a major effect on the levels and lipid composition of high density lipoproteins (HDL). LPL deficiency is inherited as an autosomal recessive trait and most commonly presents with chylomicronaemia, abdominal pain, and eruptive xanthomata. We have previously described a mutation in exon 5 of the LPL gene which results in a substitution of glutamic acid for glycine at amino acid 188. We have now assessed 16 South African LPL deficient patients from nine separate kindreds for this mutation. Nine of these probands were homozygous for the mutation and were from four families, all of Indian descent. The ancestors of these probands have their origins in villages close to Bombay, India, which suggests a common ancestral mutation for the four Indian kindreds, particularly as the mutant allele in each family carried the identical restriction fragment length polymorphism (RFLP) haplotype. The presence of at least nine affected subjects in this small community around Cape Town is evidence for a higher than expected gene frequency for LPL deficiency in this population.     

A case of Down syndrome with acute lymphoblastic leukemia and isochromosome Xp

A 3-year, 9-month-old girl with trisomy 21 was diagnosed with acute lymphoblastic leukemia (ALL). The karyotype of her leukemic cells at diagnosis-48,XX,+i(X)(p10),+21c-included an extra, structurally abnormal X chromosome as the sole acquired abnormality. While an extra X chromosome is a common abnormality in childhood ALL, it is seldom the only acquired aberration. Furthermore, an additional X chromosome that is structurally abnormal is rare, and has not been reported previously as a solitary abnormality. Here we report a novel karyotype in childhood ALL and review the eight previously described cases of ALL with an extra X isochromosome as the only acquired abnormality.     

脂质转运和脂酶水解对低密度脂蛋白的修饰作用

采用胆固醇脂转运蛋白（CETP）介导极低密度脂蛋白（VLDL）中甘油三酯（TG）与低密度脂蛋白（LDL）中胆固醇（CH）交换：再行脂蛋白脂酶（LPL）水解LDL中TG，对LDL进行修饰，引起LDL颗粒组成和大小的变化，探讨体内小而致密的LDL形成的可能途径，及易于致动脉粥样硬化（As）作用的机制。结果示CETP介导的脂质转运使LDL中TG含量增加，CH降低，颗粒直径轻微变大；再经LPL水解的共同作用，LDL中TG含量降低，颗粒变小。同时LDL中载脂蛋白B（apoB）免疫反应性也发生相应的变化，LDL中TG含量同apoB免疫反应性高度负相关。认为大而轻的A型LDL经修饰作用可转变为小而致密的B型LDL，富含TG的LDL不易于通过apoB受体途径清除，史易于氧化。     

Cytogenetic analysis of adult acute lymphoblastic leukemia including a Ph+ case surviving more than 5 years

We have performed cytogenetic analysis on 25 consecutive adult patients with previously untreated acute lymphoblastic leukemia (ALL) who were subsequently treated with the same protocol at this institution. Ten of the 25 patients studied (40%) demonstrated karyotypic abnormalities. The most frequent abnormalities were hyperdiploidy (six patients) and presence of the Philadelphia (Ph) chromosome (three patients). Univariate analysis of 12 features identified only immunophenotype as differing between patients with abnormal and normal karyotype. The cells of patients with an abnormal karyotype were more often non-B, non-T and less often T cell in phenotype. One patient initially with Ph remains cytogenetically normal in complete remission 272 weeks post diagnosis. We confirm that cytogenetic abnormalities are frequent in adult ALL. The attainment of disease free survival in Ph-positive ALL of more than 5 years with persistently normal cytogenetics demonstrates that aggressive multimodal therapy can induce long-term remissions and possible cure of this usually unfavorable situation.     

Pathophysiologie und Therapie von Lipidstoffwechselstörungen bei Nierenerkrankungen

Summary Nephrotic syndrome, uremia, hemodialysis, peritoneal dialysis, and renal transplantation are accompanied by alterations in lipoprotein metabolism (Table 1). In nephrotic patients, total cholesterol, LDL, VLDL and triglycerides are elevated, while HDL may be increased, normal, or decreased. The pathophysiology includes increased hepatic synthesis of VLDL and cholesterol, decreased activity of lipoprotein lipase, and increased urinary excretion of HDL (Fig. 1). The risk of coronary heart disease (CHD) is increased in nephrotic patients, and elevated LDL-cholesterol may contribute to this risk. Cholesterol lowering diet and drugs are indicated. Presently, Lovastatin and Simvastatin are the most potent cholesterol lowering drugs in nephrotic patients with good evidence of long-term safety. Most patients with impaired renal function or on hemodialysis have moderate hypertriglyceridemia due to decreased lipoprotein lipase activity (Fig. 2). HDL may be slightly decreased. Although the risk of CHD is increased in these patients, triglyceride lowering drugs are not indicated, since no benefit can be expected. Peritoneal dialysis is accompanied by elevated VLDL in addition to hypertriglyceridemia. Reabsorption of large amounts of glucose from peritoneal dialysis fluid increases the carbohydrate load and stimulates hepatic VLDL synthesis. Cholesterol lowering therapy may be advantageous, but the experience is very limited. Side effects of lipid lowering drugs may be aggravated in renal failure. Total cholesterol, LDL, VLDL, and triglycerides are elevated in 50% of patients following renal transplantation. Corticosteroides and cyclosporin are major causes of hyperlipidemia. Cholesterol lowering therapy is indicated since the incidence of CHD is increased. Lipid lowering diet, triple immunosuppression with low dose cyclosporin, azathioprim, and prednisone, or conversion from cyclosporin to azathioprim are valuable measures to reduce cholesterol. Low-dose lovastatin (20 mg/24 h) seems to be an effective and safe cholesterol lowering drug in renal transplantation, while higher doses may induce rhabdomyolysis.

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Abkürzungsverzeichnis NS Nephrotisches Syndrom - LDL Low Density Lipoprotein Cholesterin - VLDL Very Low Density Lipoprotein Cholesterin - HDL High Density Lipoprotein Cholesterin - KHK Koronare Herzerkrankung - HMG-CoA 3-Hydroxy-3-Methylglutaryl-Coenzym A - NIH National Institute of Health - GFR Glomeruläre Filtrationsrate     

Clinical significance of triglyceride-rich lipoproteins in metabolic syndrome

Increase in triglyceride (TG) -rich lipoproteins is one of the symptoms clustered in metabolic syndrome and is associated with increased plasma free fatty acid level derived from central obesity and insulin resistance. Increase in triglyceride (TG) -rich lipoproteins is also related to several coronary risk factors such as remnant hyperlipidemia, decreased HDL-cholesterol, elevated small dense LDL, postprandial hyperlipidemia, and hypercoagulability. The first line of treatment for hypertriglyceridemia is the modification of individual life-style, among which, restriction of over-eating and practice of regular exercise are both essential. The consideration of dietary composition, not only the quantity but also the quality of nutrients, such as fat and carbohydrate, and behavior toward diet are also important to manage abnormal lipid profile. Statins, fibrates, nicotinic acid derivatives, and EPA are the drugs recommended for the treatment of dyslipidemias in metabolic syndrome.     

Effects of short-term melatonin administration on lipoprotein metabolism in normolipidemic postmenopausal women

OBJECTIVE: To investigate the effects of short-term administration of melatonin on lipoprotein metabolism in normolipidemic postmenopausal women. METHODS: Fifteen such women received 6.0 mg melatonin daily for 2 weeks. Blood was sampled before and after treatment. We measured concentrations of total cholesterol and total triglyceride in the plasma, as well as the levels of cholesterol, triglyceride, and protein in the very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Plasma apolipoprotein levels were determined by immunoturbidimetric assay. Activities of lipoprotein lipase, hepatic triglyceride lipase, and lecithin cholesterol acyltransferase were also determined by enzymatic analysis. RESULTS: Melatonin administration significantly increased the plasma levels of triglyceride by 27.2% (P < 0.05), of VLDL-cholesterol by 37.2% (P < 0.01), of VLDL-triglyceride by 62.2% (P < 0.001), and of VLDL-protein by 30.0% (P < 0.05). However, the plasma total cholesterol level and the concentration of lipid and protein in LDL and HDL were not significantly affected. Melatonin significantly increased the plasma levels of apolipoprotein C-II by 29.5% (P < 0.005), of C-III by 17.1% (P < 0.001), and of E by 7.6% (P < 0.05). The plasma levels of apolipoprotein A-I, A-II, and B were not altered. Melatonin significantly inhibited the activity of lipoprotein lipase by -14.1% (P < 0.05), but did not significantly affect the activities of hepatic triglyceride lipase or of lecithin cholesterol acyltransferase. CONCLUSIONS: Findings indicate that melatonin increases the plasma level of VLDL particles by inhibiting the activity of lipoprotein lipase, but may not affect the plasma levels of LDL and HDL particles in postmenopausal women with normolipidemia.     

Therapeutic potential of lipase inhibitor orlistat in Alzheimer’s disease

Emerging evidences indicate that elevated cholesterol and triglyceride levels precede Alzheimer’s disease (AD) pathology. High caloric intake based on saturated fat raises hyperlipidaemia and also promotes AD pathology. As a result, strategy that limits the absorption of dietary fat and attenuates hyperlipidemia could be a useful medication for protective treatment of AD. As an active site-directed inhibitor of digestive lipases, orlistat effectively reduces dietary fat absorption and decreases total cholesterol and triglyceride levels in plasma. Orlistat also potently inhibits lipoprotein lipase, monoacylglycerol lipase and diacylglycerol lipase, which are also involved in AD causation. Taken together, orlistat inhibits lipases activities, thereby reduces dietary fat intake and ameliorates hyperlipidemia, which indicates a therapeutic potential of orlistat in protecting against AD pathology.     

The proportion of abnormal karyotypes in acute leukemia samples related to method of preparation

Bone marrow and peripheral blood were studied from 200 patients with acute leukemia [109 with acute myeloid leukemia (AML), 91 with acute lymphoblastic leukemia (ALL)] who had samples cultured for varying times and who had a mixture of chromosomally abnormal and normal cells. The mean percentage of abnormal metaphase cells increased with culture time. The peak was reached at 48 hours and declined slightly after 72 hours in culture for ALL patients. The mean percentage of abnormal cells increased up to 72 hours in culture for AML patients. In 68 patients (31 AML and 37 ALL), cytogenetic data were available from samples processed with both direct preparations and culture methods. The percentage of abnormal cells increased after culture in 49 patients (23 AML and 26 ALL), while it decreased or remained at the same level in 19 patients. For AML patients, the mean percentage of abnormal cells was significantly different between direct (38%) and cultured preparations (63%), (p less than 0.001). Seven of 9 patients with AML who showed a greater than 50% increase in abnormal cells after culture had either a t(8;21), t(15;17), or abnormalities involving 11q23. The two patients who showed a significant decrease in abnormal cells both had a translocation involving 11q13. Compared with ALL, more AML patients showed greater than 80% abnormal bone marrow metaphase cells at diagnosis or at relapse.     

Changes of serum lipoproteins during the course of human malaria (author's transl)

Triacylglycerides (TAG), total cholesterol (TC) and serum lipoproteins (SLP) were studied during the course of 12 cases of human malaria and one case of simian inui malaria. The erythrocytic schizogony induced quickly an increase of TAG, a decrease of TC and modifications of SLP such an increase of VLDL parallel with a decrease or a disappearance of HDL. These modifications, always clear-cut, were not correlated with the intensity of parasitaemia or the species of Plasmodium. They were transient but longer than those described in connection with experimental rodent malaria. The changes of HDL could be associated with defective triglyceride removal of the plasma compartment due to an inhibition of the lipoprotein lipase induced by the parasite.     

Electrophoretic screening for human apolipoprotein C-II variants: repeated identification of apolipoprotein C-II(K19T)

Screening for apolipoprotein (apo) C-II variants in the plasma of 400 students, 600 patients of a cardiological rehabilitation center, and 1200 patients of an outpatient lipid clinic by isoelectric focusing and subsequent anti-apo C-II immunoblotting led to the identification of four individuals whose plasma samples contained an apo C-II isoform with an abnormal isoelectric point. In all cases direct sequencing of PCR-amplified DNA assessed a heterozygous A to C transversion in codon 19 of the apo C-II gene which leads to the replacement of lysine with threonine. Two of the four index patients presented with moderate hypertriglyceridemia; one suffered from severe hyperlipidemia, with triglyceride levels ranging between 180 and 1900 mg/dl, depending on dietary changes. Sequencing of this proband's lipoprotein lipase gene showed no alteration compared to the wildtype sequence. A study in his family revealed that heterozygosity for apo C-II(K19T) is not associated with differences in mean lipid and lipoprotein concentrations. In conclusion, apo C-II(K19T) occurs in Germany at a frequency of approximately 1 in 550. Although this variant is not sufficient to cause hypertriglyceridemia, it may be possible that apo C-II(K19T) causes hypertriglyceridemia in the presence of additional as yet unidentified environmental and/or genetic factors.Abbreviations Apo Apolipoprotein - HDL High-density lipoprotein - HTGL Hepatic triglyceride lipase - IEF Isoelectric focusing - LPL Lipoprotein lipase - PCR Polymerase chain reaction - VLDL Very low density lipoproteins