Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholesteryl ester storage disease, caused by the loss of lysosomal acid ester hydrolase (EC 3.1.1.13), has been previously associated with hyperlipidemia and premature atherosclerosis. We identified a 23-month-old female with cholesteryl ester storage disease and characterized the plasma lipids and lipoproteins in the proband and her family. These studies illustrate several important points about this disease. First, a high index of suspicion is required to diagnose this disease since the major physical manifestation of the disorder, mild hepatomegaly, is subtle. Second, the Type II hyperlipoproteinemia in the proband is paralleled by a reduction in the concentration of high density lipoproteins. Third, analysis of the plasma lipids and lipoproteins in family members revealed both Type II and Type IV hyperlipoproteinemia with an inheritance pattern similar to that of familial combined hyperlipoproteinemia. Fourth, the parents and brother of this patient had 50% normal fibroblast acid ester hydrolase activity. These results raise the possibility that deficiency of the lysosomal acid ester hydrolase may be linked to familial combined hyperlipoproteinemia and that this enzyme deficiency may be more common than previously appreciated.
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PMID:Characterization of plasma lipids and lipoproteins in cholesteryl ester storage disease. 399 99

Although analysis of lipoprotein phenotypes is widely used to diagnose and classify the familial hyperlipidemias, an evaluation of this system as a method for genetic classification has hitherto not been published. The present study of 156 genetically defined survivors of myocardial infarction was therefore designed to examine the relationship between lipoprotein phenotypes and genetic lipid disorders. The lipoprotein phenotypes of each survivor was determined primarily by measurement of his plasma triglyceride and low density lipoprotein (LDL)-cholesterol concentrations; his genetic disorder was identified by analysis of whole plasma cholesterol and triglyceride levels in relatives. The mean levels of LDL-cholesterol discriminated statistically among the three monogenic lipid disorders; it was highest in survivors with familial hypercholesterolemia (261+/-61 mg/100 ml [mean +/-SD]); intermediate in those with familial combined hyperlipidemia (197+/-50); and lowest in those with familial hypertriglyceridemia (155+/-36) (P < 0.005 among the three groups). However, on an individual basis no lipoprotein pattern proved to be specific for any particular genetic lipid disorder; conversely, no genetic disorder was specified by a single lipoprotein pattern. This lack of correlation occurred for the following reasons: (a) individual LDL-cholesterol levels frequently overlapped between disorders; (b) in many instances a small quantitative change in the level of either LDL-cholesterol or whole plasma triglyceride caused qualitative differences in lipoprotein phenotypes, especially in individuals with familial combined hyperlipidemia, who showed variable expression (types IIa, IIb, IV, or V); (c) lipoprotein phenotypes failed to distinguish among monogenic, polygenic, and sporadic forms of hyperlipidemia; (d) clofibrate treatment of some survivors with genetic forms of hyperlipidemia caused their levels of triglyceride and LDL-cholesterol to fall below the 95th percentile, thus resulting in a normal phenotype; and (e) beta-migrating very low density lipoproteins (beta-VLDL), previously considered a specific marker for the type III hyperlipidemic disorder, was identified in several survivors with different lipoprotein characteristics and familial lipid distributions. These studies indicate that lipoprotein phenotypes are not qualitative markers in the genetic sense but instead are quantitative parameters which may vary among different individuals with the same genetic lipid disorder. It would therefore seem likely that a genetic classification of the individual hyperlipidemic patient with coronary heart disease made from a quantitative analysis of lipid levels in his relatives may provide a more meaningful approach than determination of lipoprotein phenotypes.
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PMID:Hyperlipidemia in coronary heart disease. 3. Evaluation of lipoprotein phenotypes of 156 genetically defined survivors of myocardial infarction. 435 58

Radioisotopic kinetic studies of triglyceride fatty acid synthesis from serum free fatty acids have been performed in 20 studies of normal and lipemic subjects. The lipemic subjects were characterized as having carbohydrate-responsive endogenous lipemia, and were classified as having either Type III or Type IV prebetalipoproteinemia. In the untreated state, triglyceride production was reduced relative to concentration of triglyceride when compared with the normal control population. In response to carbohydrate restriction an absolute reduction in triglyceride synthesis from free fatty acids was demonstrated. These data indicate that overproduction cannot be importantly implicated as the etiology of this form of endogenous lipemia. The patients thus represent a pathophysiological entity which is distinct from the normal physiological lipemia induced by carbohydrate feeding in which overproduction is reported to be the initiating event.
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PMID:Synthesis of plasma triglycerides in endogenous hypertriglyceridemia. 436 44

To assess the genetics of hyperlipidemia in coronary heart disease, family studies were carried out in 2520 relatives and spouses of 176 survivors of myocardial infarction, including 149 hyperlipidemic and 27 normolipidemic individuals. The distribution of fasting plasma cholesterol and triglyceride values in relatives, together with segregation analyses, suggested the presence of five distinct lipid disorders. Three of these-familial hypercholesterolemia, familial hypertriglyceridemia, and familial combined hyperlipidemia-appeared to represent dominant expression of three different autosomal genes, occurring in about 20% of survivors below 60 yr of age and 7% of all older survivors. Two other disorders-polygenic hypercholesterolemia and sporadic hypertriglyceridemia-each affected about 6% of survivors in both age groups. The most common genetic form of hyperlipidemia identified in this study has hitherto been poorly defined and has been designated as familial combined hyperlipidemia. Affected family members characteristically had elevated levels of both cholesterol and triglyceride. However, increased cholesterol or increased triglyceride levels alone were also frequently observed. The combined disorder was shown to be genetically distinct from familial hypercholesterolemia and familial hypertriglyceridemia for the following reasons: (a) the distribution pattern of cholesterol and triglyceride levels in relatives of probands was unique; (b) children of individuals with combined hyperlipidemia did not express hypercholesterolemia in contrast to the finding of hypercholesterolemic children from families with familial hypercholesterolemia; and (c) analysis of informative matings suggested that the different lipid phenotypes owed their origin to variable expression of a single autosomal dominant gene and not to segregation of two separate genes, such as one elevating the level of cholesterol and the other elevating the level of triglyceride. Heterozygosity for one of the three lipid-elevating genes identified in this study may have a frequency in the general population of about 1%, constituting a major problem in early diagnosis and preventive therapy.
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PMID:Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. 471 53

Plasma lipoprotein concentration, composition, and size were evaluated in two common familial forms of hypertriglyceridemia and compared with those in normal subjects. The very low density lipoproteins (VLDL) were triglyceride-enriched in familial hypertriglyceridemia (triglyceride/apoprotein B ratio: 25.7 +/- 8.9) as compared to normal (9.6 +/- 12.2, P < 0.001) or familial combined hyperlipidemia (9.7 +/- 3.3, P < 0.001). The diameter of VLDL was larger in familial hypertriglyceridemia (3.27 +/- 0.28 pm) than in familial combined hyperlipidemia (2.87 +/- 0.16 pm, P < 0.02). Although in familial hypertriglyceridemia VLDL tended to be larger, and in familial combined hyperlipidemia VLDL tended to be smaller than normal (3.08 +/- 0.48 pm), neither of these differences were significant. While VLDL was normally distributed in the control population, the size was skewed to larger particles in familial hypertriglyceridemia with fewer small particles (P < 0.05) and skewed to smaller particles in familial combined hyperlipidemia with fewer large particles (P < 0.05). VLDL was reciprocally related to low density lipoproteins (LDL) in familial combined hyperlipidemia (r = -0.80 to -0.87) suggesting that the concentrations of these individual lipoprotein groups were somehow interrelated. There was no significant relationship between these two lipoprotein classes in familial hypertriglyceridemia or in normals. In familial combined hyperlipidemia, the apoprotein A-I/A-II ratio was below normal (P < 0.01) suggestive of low HDL(2) levels. This change in apoprotein composition was independent of VLDL or LDL concentration. In familial hypertriglyceridemia, high density lipoprotein (HDL) cholesterol was reduced (33% below mean normal) and HDL triglyceride was increased (by 46%), while the concentration of apoA-I and apoA-II was normal. VLDL triglyceride was inversely related to HDL cholesterol in familial hypertriglyceridemia (r = -0.74, P < 0.005), but not in familial combined hyperlipidemia. The large, triglyceride-enriched VLDL observed in familial hypertriglyceridemia is compatible with the reported increase in VLDL triglyceride synthesis seen in this disorder. The increase in VLDL apoprotein B synthesis previously reported in familial combined hyperlipidemia was associated with VLDL of normal composition. The changes in HDL cholesterol in these two disorders might reflect exchange of triglyceride between VLDL and HDL or could be related to transfer of surface components during the catabolism of VLDL. The reciprocal relationship between various components of VLDL and LDL seen in familial combined hyperlipidemia, but not in familial hypertriglyceridemia or in normal subjects, might provide some insight into the pathological abnormalities in these disorders. The differences between these two common familial forms of hypertriglyceridemia provide further support that they are distinct entities.-Brunzell, J. D., J. J. Albers, A. Chait, S. M. Grundy, E. Groszek, and G. B. McDonald. Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia.
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PMID:Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia. 640 42

This study investigates the pedigree of 508 individuals over five generations identified by an individual with hypertriglyceridemia, familial hypercholesterolemia, and a IIb lipoprotein electrophoretic phenotype. The sample of 378 living individuals studied extensively for risk factors and disease status was distributed among maternal (170) and paternal (176) relatives and the codescendants (32) of the index case. It was found that the distributions of the plasma lipid and lipoprotein abnormalities in the different subsets of the kindred were consistent with the presence of two separate hereditary lipid disorders: familial hypercholesterolemia on the paternal side and familial hyperprebetalipoproteinemia on the maternal side. This combination of disorders with a possible contribution from factors influencing glucose metabolism was associated with high frequency of hypercholesterolemia and its clinical manifestations and of cardiovascular morbidity among the codescendants. An interaction effect is suggested as an explanation for the unusually high prevalence of hyperlipidemia among the codescendants and for the presence of a IIb phenotype in the index case.
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PMID:Interaction of two lipid disorders in a large French-Canadian kindred. 682 93

The present investigation was designed to examine the influence of genetic Type IV hyperlipoproteinemia on the metabolism of lipids in response to estrogen exposure. The influence of 17-Beta-estradiol * was examined in a dose-response study over a range of hormone concentration from 10 to 100 pg/ml in genetic hyperlipidemic Zucker rats. In oophorectomized female rats, replacement levels of plasma estradiol of 40 pg/ml resulted in maximal hypertriglyceridemia of approximately 500 mg/dl representing a 5-fold exaggeration of that observed in control genetically norm-lipemic animals. This hypertriglyceridemia was associated with an increased production of triglyceride (TG) in excess of clearance, with a resulting production: clearance ratio of approximately 1.5. Exposure to maximum blood levels of estradiol, approximately 100 pg/ml, resulted in sub-normal levels of plasma TG (-145 mg/dl) in association with a reduced production: clearance ratio of approximately 0.36. In contrast to the marked hypocholesterolemic response to maximum estrogen exposure seen in normolipemic animals, the genetic Type IV hyperlipemic animal failed to demonstrate reduced plasma cholesterol concentration. This phenomenon was related to a rise in plasma LDL concentration in conjunction with parallel reduction in plasma HDL2 levels.Thus, an abnormal ratio of excessive LDL: HDl emerged in response to estrogen exposure in this model of human Type IV lipemia. This observation suggests that the genetic predisposition of the host may be critical to both the quantitative as well as the qualitative response to estrogen.
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PMID:Influence of genetic hyperlipemia in the Zucker rat upon the lipemic response to graded estradiol exposure. 707 97

Turnover kinetics of triglycerides (TG) and apolipoprotein-B (apo-B) of plasma very low density lipoprotein (VLDL) and their relationship to plasma VLDL composition and VLDL apo-B conversion to low density lipoprotein (LDL) were determined in age and weight-matched groups of normolipemic (NL) healthy subjects, patients with familial combined hyperlipidemia (FCHL) and patients with familial hypertriglyceridemia (FHTG). In NL subjects, a significant correlation as observed between VLDL TG or VLDL apo-B turnover rate and its circulating mass, suggesting that the plasma level of VLDL was determined by the secretion rate of VLDL TG and apo-B. The positive significant correlation between VLDL TG and apo-B also suggests that the production of these moieties was integrated at the synthetic and/or secretory sites to maintain the ratio of TG to apo-B in plasma VLDL. In moderately obese NL subjects, proportionate increases in VLDL TG and apo-B turnover rates resulted in enhanced secretion of VLDL particles. Both groups with genetic hypertriglyceridemia had increased VLDL TG and VLDL apo-B turnover rates. This increase accounted for the increase in circulating VLDL TG and apo-B mass. In patients with FCHL, turnover rates of VLDL TG and apo-B were equally increased, hence, the ratios between major VLDL constituents were within normal limits. On the other hand, the increase in VLDL TG turnover in patients with FHTG was disproportionately greater than that of apo-B resulting in a higher ratio of TG to other VLDL components. In NL subjects, approximately 72% of VLDL apo-B released into plasma was converted to LDL. This conversion correlated positively with VLDL apo-B turnover rate and inversely with VLDL TG turnover rate. Formation of LDL from VLDL was significantly greater in the obese individuals. In FCHL, conversion of VLDL to LDL represented the major pathway for VLDL apo-B catabolism. The increased VLDL apo-B load was predominantly catabolized to LDL. The greater increase in VLDL TG turnover relative to apo-B in FHTG, on the other hand, resulted in a smaller fraction of VLDL apo-B recovered in LDL, most of the VLDL apo-B being removed via a pathway that did not involve this conversion. We conclude that the composition and metabolic fate of plasma VLDL may be greatly influenced by the secretion rates of VLDL TG and apo-B. If VLDL conversion to LDL and the subsequent catabolism of the latter provides a major route for delivery of cholesterol ester to peripheral tissues, then the increased LDL production in FCHL compared to FHTG may account for a higher cardiovascular risk.
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PMID:Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein-B kinetics in man: normolipemic subjects, familial hypertriglyceridemia and familial combined hyperlipidemia. 726 76

Interrelationships between pregnancy, hypertriglyceridemia, and pancreatitis were assessed in three women with familial hypertriglyceridemia. One subject had known familial hypertriglyceridemia, familial type V hyperlipoproteinemia, prior to conception. In this woman a progressive increase in triglyceride levels to more than 3,000 mg/dl during the first two trimesters required dietary intervention and hospitalization at 28 weeks' gestation. Use of an isocaloric National Institutes of Health type V diet reduced triglyceride levels to less than 900 mg/dl; the pregnancy was uneventful with term delivery of a healthy neonate. The familial hypertriglyceridemia was covert in the other two women until term. In one subject, subsequently shown to have familial type V, acute hemorrhagic pancreatitis with a pancreatic pseudocyst, shock, and hypocalcemia developed at 39 weeks' gestation; the neonate was safely delivered, and the mother survived. In the second, entirely asymptomatic subject, triglyceride levels greater than 5,000 mg/dl were discovered incidentally at term cesarean section during delivery of a healthy neonate. With a fat restricted diet, plasma triglyceride levels abruptly fell post partum to less than 500 mg/dl, and subsequent studies revealed familial type III hyperlipoproteinemia. Routine quantitation of plasma cholesterol and triglyceride levels or simple visual examination of fasting plasma for triglyceride-induced opacity or "milky" appearance should be done during early pregnancy. This would allow the obstetrician to identify women with severe familial hypertriglyceridemia prior to the superimposition of the physiologic hyperlipidemia of pregnancy upon familial hypertriglyceridemia with resultant, and often catastrophic, acute pancreatitis.
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PMID:Pancreatitis, familial hypertriglyceridemia, and pregnancy. 735 61

The fasting activity of adipose tissue lipoprotein lipase has been previously reported to be either normal or reduced in subjects with a primary form of hypertriglyceridemia. The postprandial activity of adipose tissue lipoprotein lipase has not been previously reported in these subjects. In subjects with primary hypertriglyceridemia the fasting lipoprotein lipase activity eluted from pieces of adipose tissue by heparin and the enzyme activity present in extracts of acetone--ether tissue powders were similar to the level of enzyme activity found in normal subjects. There also was no difference in the postprandial adipose tissue heparin-elutable lipoprotein lipase activity between these two groups when measured after high carbohydrate feeding. When the subjects with primary hypertriglyceridemia were further subdivided by genetic diagnosis, there was no difference in the level of adipose tissue lipoprotein lipase of subjects with familial hypertriglyceridemia, familial combined hyperlipidemia, or in those in whom no specific genetic diagnosis could be made. The change in lipoprotein lipase activity after feeding was inversely related to the fasting enzyme level in both the normal subjects (r = -0.58, p less than 0.05, n = 12) and the hypertriglyceridemic subjects (r = -0.92, p less than 0.01, n = 11). In the normal subjects, the plasma triglyceride response to feeding correlated inversely with the postprandial change in lipoprotein lipase activity (r = -0.76, p less than 0.02, n = 12). Adipose tissue lipoprotein lipase activity in patients with primary lipoprotein lipase deficiency was markedly reduced in the fasting state and remained essentially zero after feeding. This suggests that a functional role exists for the enzyme activity as measured.
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PMID:Postprandial adipose tissue lipoprotein lipase activity in primary hypertriglyceridemia. 737 36


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