Familial and acquired type V hyperlipoproteinemia.

The nature of Type V hyperlipoproteinemia including mode of presentation, prominent clinical and biochemical features, and genetics, was examined in 29 adults presenting with the Type V lipoprotein phenotype. Initially 23 of the 29 patients had various metabolic stimuli (diabetes out of control, estrogenic agents, pancreatitis, ethanolism) superposed on their acute hypertriglyceridemia. After metabolic stabilization, 17 of the 29 subjects were shown to have familial hypertriglyceridemia. In the 17 kindreds with familial hypertriglyceridemia, the lack of a specific, distinctive genetic marker for the Type V genotype and for the Type IV genotype restricts the conclusion that the pattern of inheritance was consistent with an autosomal dominant trait.     

Plasmapheresis in conjunction with the dextran sulfate cellulose column for hypertriglyceridemic patient: a comparison with familial hypercholesterolemia.

For assessment of the usefulness of a dextran sulfate cellulose (DSC) column in the conduct of plasmapheresis (DSC lipoprotein adsorption, DSC-LA) for patients with hypertriglyceridemia on hemodialysis, a study was conducted to determine whether the adsorption of lipoproteins on a column varies in response to a variation in the lipoprotein composition. A patient with type V hyperlipoproteinemia on hemodialysis, a patient with type IIa homozygous, and a patient with type IIa heterozygous familial hypercholesterolemia were used in this study. In all patients, apolipoprotein B- and E-containing lipoproteins were removed preferentially by a DSC column. Following DSC-LA, abdominal pain before DSC-LA in a patient with type V hyperlipoproteinemia subsided, and regression of tuberous and tendinous xanthomas was induced in familial hypercholesterolemia. In cases of hyperlipoproteinemia, this column thus appears to exert a therapeutic effect regardless of the type of disease.     

Further resolution and comparison of the heterogeneity of plasma low-density lipoproteins in human hyperlipoproteinemias: type III hyperlipoproteinemia, hypertriglyceridemia and familial hypercholesterolemia

The heterogeneity of the plasma low-density lipoproteins (LDL) in subjects with type III hyperlipoproteinemia (3 cases), with hypertriglyceridemia (4 cases) and with the heterozygous form of familial hypercholesterolemia (FH, 4 cases) has been evaluated using a new, high resolution equilibrium density gradient ultracentrifugation procedure. The mass distribution profile, physicochemical properties, particle heterogeneity and apoprotein B content of a series of 13 LDL subfractions was examined in the 3 hyperlipidemic groups and the data were compared with those reported earlier in normolipidemic subjects. In FH, LDL mass was distributed as a narrow peak of d approximately 1.031-1.034 g/ml, whereas the distribution in hypertriglyceridemia was markedly asymmetric with a single peak of elevated density (d approximately 1.037-1.043 g/ml); the distribution in type III subjects was distinguished by its bi- or trimodal nature and broad profile. The chemical composition of LDL gradient subfractions in FH and in hypertriglyceridemia markedly resembled that of the respective parent LDL of d = 1.019-1.063 g/ml, displaying elevated proportions of cholesteryl ester in FH and of protein in hypertriglyceridemia. LDL subfractions in type III disease were enriched in free cholesterol. The Stokes diameters of LDL particles in corresponding subfractions from the 3 hyperlipidemic states were similar; however, whereas a single particle species was characteristic of each LDL subfraction in both FH and in our normolipidemic group, 2 species were frequently present in each subfraction in both type III and type IV diseases; in addition, subfractions from type III subjects occasionally exhibited 3 size species. Apolipoprotein B-100 was the predominant protein component in LDL subfractions from all 3 hyperlipidemic groups. Plasma LDL consist then of multiple particle species which constitute a particularly complex spectrum in type III hyperlipoproteinemia and in hypertriglyceridemia. The origin(s) of such particle subspecies is indeterminate at present; moreover, they may differ in their intravascular metabolism, in their degradation in tissues and in their relative atherogenicities.     

Increased risk for vitamin A toxicity in severe hypertriglyceridemia

A 48-year-old woman with malabsorption and type V hyperlipoproteinemia developed hypervitaminosis A with a total plasma vitamin A level of 871 micrograms/dL during therapy with an oral dosage of 18,000 retinol equivalents (60,000 IU) daily. Twelve percent of the total plasma retinol was found to be transported in the chylomicron-very low density lipoprotein (VLDL) fraction, which does not contain retinol-binding protein. For comparison, concentrations of retinyl esters and retinol were determined in nine patients with type V hyperlipoproteinemia and nine control subjects, none of whom were using vitamin A supplements. Both retinyl esters and retinol were significantly elevated in the group with hyperlipoproteinemia (p less than 0.0005 in both cases). Eight of these nine patients had retinol present in the chylomicron-VLDL fraction, whereas retinol was not detectable in this fraction in any of the nine normal controls. The data suggest that patients with severe hypertriglyceridemia associated with type V hyperlipoproteinemia are at increased risk for hypervitaminosis A.     

Familial hypertriglyceridemia: studies in 130 children and 45 siblings of 36 index cases

Studies in 130 children and 45 siblings of 36 propositi with familial hypertriglyceridemia were carried out to evaluate the incidence, mechanism of transmission, and results of early therapy of hypertriglyceridemia in a pediatric-young adult population. Twenty-three of 113 children (ages 1–20) and 10 of 17 children (ages 20–35) from these kindreds had type IV hyperlipoproteinemia with primary elevations of triglycerides. Twenty-nine of the probands' 45 siblings had primary elevations of triglycerides. Although plasma cholesterol levels in the 130 children and 45 siblings were normally distributed, plasma triglycerides in both groups did not fall into a single log-normal distribution, and more nearly represented a bimodal pattern. Weight reduction and the NIH type IV diet were effective in reducing triglyceride levels to normal in most children. Complete family screening in kindreds with familial hypertriglyceridemia makes possible early diagnosis and amelioration of hypertriglyceridemia in an appreciable number of children.     

Primary type V hyperlipoproteinemia. A descriptive study in 32 families.

We have studied 32 kindreds identified by propositi with primary type V hyperlipoproteinemia. The clinical presentation, metabolic associations, and natural history confirm the distinctiveness of primary type V hyperlipoproteinemia from other lipoprotein abnormalities. Although the underlying defect(s) remains unknown, several factors such as obesity, alcohol, drugs, and diet are able to modify the glyceridemia, the major manifestation of this disorder. Abnormalities of postheparin lipolytic activity or its subfractions do not appear to be involved in the pathogenesis of primary type V. The prevalence of hyperuricemia, diabetes, pancreatitis, and xanthomatosis appears high among the 32 propositi; the last two entities are much less prevalent in the relatives, even among those relatives classified as hyperglyceridemic. There is no evidence in these families of excessive coronary artery disease prevalence. Triglyceride levels are positively associated with age in this population, especially among women. Average triglyceride levels were lower for women than for men before age 50.     

Hemorrheologic abnormalities in defined primary dyslipoproteinemias with both high and low atherosclerotic risks

Dyslipoproteinemias are associated with hemorrheologic abnormalities (elevated fibrinogen concentration, higher viscosity of plasma and blood). Epidemiologic data suggest that not only elevated lipoprotein concentrations (eg, low-density lipoprotein [LDL] cholesterol), but also hemorrheologic abnormalities could causally be involved in the atherosclerotic process. To elucidate potential effects of hemorrheological disturbances, we investigated patients suffering from primary hyperlipoproteinemias with both low (familial hypertriglyceridemia, n = 25) and high (type III hyperlipoproteinemia, n = 21; familial hypercholesterolemia, n = 19; mixed hyperlipoproteinemia, n = 19) atherosclerotic risk, as well as healthy controls (n = 49) in a cross-sectional design. Dyslipoproteinemias were classified by lipoprotein measurements (using ultracentrifugation), family history, and apolipoprotein E phenotype. Hemorrheology was characterized by the measurement of fibrinogen concentration, viscosity of plasma and blood at different shear rates, and red cell aggregation (RCA) at stasis and low shear. Fibrinogen concentration was lower in controls (2.38 +/- 0.09 g/L) compared with familial hypercholesterolemia (3.19 +/- 0.19 g/L), to type III hyperlipoproteinemia (3.02 +/- 0.12 g/L), to familial hypertriglyceridemia (2.95 +/- 0.21 g/L) and to mixed hyperlipoproteinemia (3.01 +/- 0.12 g/L) (P < .05, respectively) without differences between dyslipoproteinemia groups. Plasma viscosity was higher in patients with type III hyperlipoproteinemia (1.42 +/- 0.03 mPas), with familial hypertriglyceridemia (1.47 +/- 0.04 mPas), and with mixed hyperlipoproteinemia (1.43 +/- 0.02 mPas) compared with controls (1.29 +/- 0.01 mPas) (P < .05, respectively). After including 6 lipoprotein parameters in a general linear model, plasma viscosity, blood viscosity, and RCA were higher in familial hypertriglyceridemia compared with healthy controls and familial hypercholesterolemia (P < .05, respectively). As most of the hemorrheologic abnormalities were still significant after adjusting for lipoprotein concentrations, they seem to be at least partly independent from direct lipoprotein effects. Hemorrheologic abnormalities in familial hypertriglyceridemia (low atherosclerotic risk) were at least as marked as in dyslipoproteinemias with high atherosclerotic risk, suggesting that it might be most important to determine lipoprotein concentrations and to define exactly the type of dyslipoproteinemia for estimating the individual cardiovascular risk in these patients.     

Plasma apolipoprotein CII levels in hypertriglyceridemia

It is known that hypertriglyceridemia is associated with the elevation of plasma apolipoprotein CII (apoCII). In an attempt to look at the relationship between the two, the present study was conducted. We examined 30 patients with hypertriglyceridemia (TG, 210 to 9,127 mg/dL) and ten normolipidemic controls. Hypertriglyceridemic patients included 7 of type I hyperlipoproteinemia (HL), 17 of type IV, and 6 of type V. Plasma apoCII was measured by the single radial immunodiffusion method. Major cause for any difference in plasma apoCII could be attributed to differences in the TG-rich lipoproteins. Since a model for the lipoprotein structure indicates that TG-rich lipoproteins are spherical, with apoCII as a surface component and TG as a core substance, we calculated the square roots and the cubic roots of the values of apoCII and TG to make comparison possible. When the two variables were plotted on the X and Y axes respectively, we obtained the regression line of square root of apoCII = 0.37 X 3 the square root of TG - 0.03 with a correlation coefficient of r = .95 (P less than 0.001). The result indicates that a lipoprotein structural model accounts well for the relationship between apoCII and TG. Although a previous report suggested a compensatory increase of apoCII in lipoprotein lipase deficiency, our patients with type I HL had apoCII levels similar to those who had comparable levels of plasma TG.     

Apolipoprotein E allele frequencies in non-insulin-dependent diabetes mellitus with hypertriglyceridemia (type IIb, III, IV, and V hyperlipoproteinemia).

We examined apolipoprotein E (apo E) allele frequencies in non-insulin-dependent diabetes mellitus (NIDDM) patients with normolipidemia or various types of hypertriglyceridemia to elucidate the association of the apo E alleles with hypertriglyceridemia in NIDDM. NIDDM patients with normolipidemia (N = 134) or hypertriglyceridemia [type IIb hyperlipoproteinemia (HLP) (N = 42), III HLP (N = 7), IV HLP (N = 96), and V HLP (N = 8)] were randomly selected from our Diabetic Clinics. Apo E phenotypes (genotypes) were determined by our rapid flat-gel isoelectric focusing method. The frequency of the epsilon 4 allele was significantly higher in the type IIb (20.2%, P less than .01) and V (25.0%, P less than .05) HLP patients than in the normolipidemic patients (8.9%), whereas the frequency of the epsilon 3 allele was significantly (P less than .025) lower in the type IIb HLP patients (78.6%) than in the normolipidemic patients (89.2%). The frequency of the epsilon 2 allele was significantly higher in the type III (64.3%, P less than .001) and IV (5.2%, P less than .05) HLP patients than in the normolipidemic patients (1.9%), whereas the frequency of the epsilon 3 allele was significantly lower in the type III (28.6%, P less than .001) and IV (82.8%, P less than .05) HLP patients than in the normolipidemic patients. Thus, it has proven that the epsilon 2 allele is related to type III and IV HLP in NIDDM, whereas the epsilon 4 allele is related to type IIb and V HLP in NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Estrogen-induced pancreatitis in patients with previously covert familial type V hyperlipoproteinemia

Previously covert familial Type V hyperlipoproteinemia became overt in three women and one man, when pancreatitis followed postmenopausal and postprostatectomy estrogen administration. Exogenous and endogenous hypertriglyceridemia were severely exacerbated, carbohydrate tolerance worsened, and activity of postheparin lipolytic enzymes were depressed by estrogenic “therapy”. Amelioration of pancreatitis, decrements in hyperglyceridemia and hyperglycemia, and increments in postheparin lipolytic activities followed cessation of estrogens.     

Diabetic lipemia with eruptive xanthomatosis in a lean young female with apolipoprotein E4/4

Eruptive xanthomas in adults are usually indicative of chylomicronemia. Although diabetes mellitus is the most common secondary cause of chylomicronemia, which is designated as diabetic lipemia, the clinical characteristics of diabetes with regard to development of xanthomas are not well defined. In this paper, we describe a young female who displayed eruptive xanthomas as an initial manifestation of diabetic lipemia. The patient was a 20-year-old female with a body mass index of 18.9 kg/m2 and Marfanoid appearance. Her past history was unremarkable, except for patent ductus arteriosus and mild mental retardation. She was admitted to our division for eruptive xanthomas on the extremities and marked hyperglycemia (random glucose, 520 mg/dl) and hypertriglyceridemia (6880 mg/dl). She was diagnosed with Type 2 diabetes based on the positive family history of diabetes, residual secretory capacity of insulin, and absence of autoantibodies related to Type 1 diabetes. Based on the increase in the concentrations of both chylomicrons and very low density lipoproteins, type V hyperlipoproteinemia was diagnosed. After the initiation of insulin therapy, both hypertriglyceridemia and eruptive xanthomas subsided, without administering any hypolipidemic agents. Minimal model analysis of a frequently sampled intravenous glucose tolerance test revealed severe insulin resistance, despite the absence of obesity. Post-heparin lipoprotein lipase (LPL) activity was moderately decreased, and common mutations in the LPL gene were not demonstrated by genetic screening. The apolipoprotein E phenotype was E4/4, which is known to be associated with type V hyperlipoproteinemia. Hypoadiponectinemia of 1.7 microg/ml was also revealed, which may, in part, account for the insulin resistance and decreased LPL activity. In conclusion, the clustering of apolipoprotein E4/4 and hypoadiponectinemia, in addition to insulin resistance and poor glycemic control, might have resulted in hypertriglyceridemia with eruptive xanthomatosis in this subject.     

Pediatric familial type III hyperlipoproteinemia.

Familial type III hyperlipoproteinemia is almost always first diagnosed in adults; the two 16-yr-old probands with type III in this report represent only the fifth and sixth children reported with the disorder. S.E., a 16-yr-old female, and C.H., a 21-yr-old male, (with palmar xanthomas at age 16) had beta-migrating abnormal very low density lipoproteins (beta-VLDL), density less than 1.006. S.E.'s brother (age 21) and mother (age 57) had type III; her grandmother had beta-VLDL and elevated triglycerides, and a maternal uncle had type IV hyperlipoproteinemia. C.H.'s father had type III; a sister and paternal aunt had type IV hyperlipoproteinemia. It is important to consider the diagnosis of type III hyperlipoproteinemia in the pediatric age group, particularly in children from families with type III hyperlipoproteinemia.     

Clearance defects in primary chylomicronemia: a study of tissue lipoprotein lipase activities

Tissue and postheparin lipoprotein lipase (LPL) activities were assayed in a heterogeneous group of eight chylomicronemic subjects ranging in age from 15 years to 55 years. Three patients, presenting with the classical genetic and clinical features of type I hyperlipoproteinemia, had virtually absent adipose tissue LPL activity and markedly reduced muscle LPL activity (between 5% and 20% of normal). A fourth patient, with a similar but more benign lipoprotein and clinical phenotype, showed reduced adipose tissue LPL activity (10% of control) but retained essentially normal muscle enzyme. This patient represents a variant form of familial LPL deficiency. Two of the four remaining patients presented with typical features of adult type V hyperlipoproteinemia associated with familial hypertriglyceridemia (type IV and V phenotypes) in first-degree relatives. Adipose tissue LPL activities were 25% to 35% of the control mean in these patients, but muscle activities were normal or elevated. A third patient had suggestively similar tissue enzyme levels, but a family study could not be carried out. The eighth patient presented with a brittle type V phenotype, normolipidemia in the two first-degree relatives available for study and normal lipolytic activity in adipose tissue, muscle, and postheparin plasma assayed against a 14C-triolein substrate. An oral fat load in this patient, however, led to a marked but transient increase in light scattering suggesting defective clearance. Mixing experiments in vitro using a chylomicron substrate strongly suggested an extrinsic defect of lipolysis due to the inhibitory effect of excess very low density lipoprotein peptides, presumably apo C-III.(ABSTRACT TRUNCATED AT 250 WORDS)     

Abnormal preponderance of sialylated apolipoprotein CIII in triglyceride rich lipoproteins in type V hyperlipoproteinemia

Triglyceride rich lipoproteins contain apolipoproteins (apo) CII and CIII. Apo CII and CIII activate and inhibit tissue lipoprotein lipase, respectively. Apo CIII is a glycoprotein containing 0, 1 or 2 moles of sialic acid (designated apo CIII₀, CIII₁ and CIII₂, respectively). This study was designed to determine whether an abnormal distribution of these biologically active apoproteins occurred in triglyceride rich lipoproteins isolated from hypertriglyceridemic individuals. Triglyceride rich lipoproteins were isolated by preparative ultracentrifugation from 10 patients with primary type V hyperlipoproteinemia, eight patients with primary type IV hyperlipoproteinemia, and 11 normal healthy normolipidemic matched control subjects. After delipidation with tetramethyl urea, apo CII and CIII subspecies were separated by analytical isoelectric focussing with a pl range between 3.5 and 5.0. This technique allows a clear separation of apo CIII₀ from its sialylated subspecies and also from apo CII. The ratios of the individual apo CIII subspecies to each other and to apo CII were calculated from densitometric scanning of the stained gels. Desialylated apo CIII₀ comprised 3.3 ± 1.9% (M ± SD.) of total apo CIII in patients with type V hyperlipoproteinemia and was significantly lower (p = 0.0001) than the proportion found in normal subjects (14.3 ± 5.9%) and patients with primary type IV hyperlipoproteinemia (16.7 ± 6.2%). Apo CIII₁ comprised 62.4 ± 5.9% of total apo CIII in type V patients being significantly higher than that in normal subjects (52.6 ± 6.9%; p = 0.003) and patients with primary type IV hyperlipoproteinemia (47.1 ± 3.7%; p = 0.0001). Apo CIII₂ as percent of total apo CIII was similar in the three groups. The distribution of the apo CIII subspecies in patients with primary type IV hyperlipoproteinemia was similar to control subjects. In patients with type V hyperlipoproteinemia, the ratio of apo CIII₀; CII (0.11 ± 0.05) was significantly lower than normal (0.47 ± 0.26; p = 0.002), and also lower than the mean ratio observed in patients with primary type IV hyperlipoproteinemia (0.60 ± 0.25; p = 0.0001). Apo CIII₁;CII ratio in type V hyperlipoproteinemia (2.24 ± 0.58) was significantly higher than normal (1.64 ± 0.41; p = 0.02) and type IV hyperlipoproteinemia (1.67 ± 0.32; p = 0.047). Apo CIII₂:CII ratio was similar in the three groups. Total apo CIII:CII ratio in types IV and V (3.5 ± 0.86 and 3.55 ± 0.66, respectively) was higher than normal (3.15 ± 0.83), but the differences were not statistically significant. These data indicate that type V hyperlipoproteinemia is associated with an abnormal preponderance of sialylated to the desialylated apo CIII in triglyceride rich lipoproteins. Further work is needed to define the precise mechanism(s) responsible for this abnormality.     

Metabolic effects of exercise in patients with type IV hyperlipoproteinemia

Metabolic responses to 30 minutes of submaximal exercise were investigated in 11 healthy control subjects and 6 patients with type IV hyperlipoproteinemia (endogenous or essential hypertriglyceridemia). All subjects were male and ranged in age from 35 to 55 years. Before exercise they fasted overnight for at least 12 hours.

The relative work performed, judged by the levels in heart rate and cardiac output on exercise, was comparable in the two groups, and the effects of exercise were qualitatively similar. Plasma glucose and triglyceride levels showed little change. Plasma concentration of cholesterol increased at the end of exercise by approximately 13 percent above control values compared to a concomitant increase in hematocrit of 3 percent. Plasma free fatty acid levels fell as exercise started and then returned to normal valves at the end of the 30 minutes of exercise; they then increased markedly after exercise but returned subsequently to control levels after 45 minutes.

In response to muscular exercise, therefore, both control subjects and patients with type IV hyperlipoproteinemia significantly increase plasma cholesterol concentration. Subjects with hyperlipoproteinemia appear to mobilize free fatty acids in a normal manner for energy purposes, and the excess release of free fatty acids during exercise is apparently not derived from the abundantly circulating triglycerides; the latter were not altered by submaximal exercise.     

Hyperlipoproteinemia, diabetes, and oxygen affinity of hemoglobin.

Oxyhemoglobin dissociation curves (ODC) were performed on blood from diabetic and nondiabetic subjects with and without hypertriglyceridemia. P50 at in vivo pH was slightly lower than normal in normolipemic diabetics (25.7 versus 26.6 mmHg, p less than 0.05), in spite of increased red cell 2,3-diphosphoglycerate concentration (15.4 versus 14.4 mumole/g Hg, p less than 0.025). P50 at in vivo pH in diabetics with moderately elevated very low density lipoproteins (VLDL)--Type IV hyperlipoproteinemia (HLP)--was likewise found to be slightly lower than normal (25.5 versus 26.6 mmHg, p less than 0.05). In contrast, diabetics with pronounced hyperlipemia due to accumulation of chylomicrons (type I HLP) or due to accumulation of chylomicrons (type I HLP) or due to accumulation of chylomicrons as well as VLDL (type V HLP) showed markedly increased hemoglobin--oxygen affinity (P50:21.1 versus 26.6 mmHg, p less than 0.001). The change in the ODC of normolipemic diabetics is considered to be an expresssion of the presence of an increased proportion of a hemoglobin fraction (Hb Alc) with increased oxygen affinity. The additional change in the ODC of the hyperlipemic patients is thought to be secondary to accumulation of triglyceride-rich particles for the following reasons: (1) a similar increase in oxygen affinity of hemoglobin was demonstrated in familial type I HLP of nondiabetic subjects; (2) normal red cells increased their oxygen affinity when incubated in lactescent plasma; (3) in both acquired types I and V HLP the disappearance of HLP was followed by a normalization of the ODC.     

Severe acute pancreatitis associated with hyperlipidemia: report of two cases and review of the literature in Japan

Two cases of severe acute pancreatitis associated with type V hyperlipoproteinemia are reported. A 39-year-old obese woman was hospitalized with continuous severe abdominal pain. The diagnosis was made on the day of admission to our hospital, and treatment using continuous regional arterial infusion of a protease inhibitor and an antibiotic was performed with good results. The other patient was a 35 year-old woman in the 35th week of pregnancy, and a diagnosis of gestational hyperlipidemic pancreatitis was made on the day of onset. She was treated supportively using intravenous hyperalimentation, protease inhibitors, and antibiotics. She recovered from the acute pancreatitis and delivered a healthy term infant. It is difficult to diagnose acute pancreatitis in patients with type V hyperlipoproteinemia, because even when serum amylase levels are high, the value is reduced by high serum triglycerides. Early diagnosis was achieved in both of the present cases, and early intensive therapy was performed, which may be of the utmost importance in saving the life of a patient.     

The hepatocyte and type IIA and IIB hyperlipoproteinemia: A morphometric study

We obtained liver biopsies in 4 patients with type IIA and 7 patients with type IIB hyperlipoproteinemia, and also in 7 healthy controls. A morphometric analysis of liver tissue was carried out by light and electron microscopy. Structural alterations of the hepatocyte and its organelles in type IIA and IIB hyperlipoproteinemia seem to fall into different categories: smaller nuclei, enlarged peroxisomes and altered mitochondria are found in both types of hyperlipoproteinemia, while an increase in the volume of hepatocytes is found only in type IIA. The enlargement of liver peroxisomes in untreated hyperlipoproteinemia is noteworthy, since it has been considered as a marker of the liver toxicity of lipid-lowering drugs.     

Low density lipoprotein (LDL) binding affinity for the LDL receptor in hyperlipoproteinemia.

We measured the binding affinity of low density lipoprotein (LDL) for the LDL receptor in patients with various types of hyperlipoproteinemia and investigated the effects of LDL lipid composition and particle size on receptor affinity. LDL (1.019 < d < 1.063) was isolated by sequential ultracentrifugation from the serum of normolipidemic controls and patients with hyperlipoproteinemia. Patients with type IIa hyperlipoproteinemia had LDL with a similar receptor affinity to that of normal LDL. However, patients with hypertriglyceridemia (type IIb and type IV hyperlipoproteinemia) had LDL with a low receptor affinity, and the degree of the reduction in affinity paralleled the severity of the hypertriglyceridemia. The LDL of hypertriglyceridemic patients was rich in protein and triglycerides, had a low content of cholesterol and phospholipids, and was smaller than normal, thus resembling the atherogenic lipoprotein known as small, dense LDL. These abnormalities were observed even in patients with mild hypertriglyceridemia regardless of their serum cholesterol levels. The degree of alteration in LDL lipid composition and particle size was strongly associated with the reduction of LDL receptor affinity. We also examined the effects of two lipid-lowering agents (bezafibrate and probucol) on the characteristics of LDL. LDL receptor affinity was only improved when the lipid composition and particle size were normalized by drug therapy. Although it has been reported that decreased cholesteryl ester transfer protein (CETP) activity results in the formation of small LDL, plasma CETP activity was normal in the hyperlipoproteinemic patients and the normalization of LDL characteristics by drug therapy was not accompanied by an increase of CETP activity. Our results suggested that an abnormal lipid composition and/or small particle size might cause a decrease in the receptor affinity of LDL. These structural and functional abnormalities were reversed by drug therapy, underlining the importance of treating hypertriglyceridemia for the prevention of atherosclerosis.     

Hyperlipoproteinemia and pancreatitis

A prospective study was begun in 1969 to investigate the relationship between hyperlipoproteinemia and pancreatitis. Ten patients were observed at the Cleveland Clinic Hospital. All had discrete, recurrent, acute pancreatitis with typical pain, hyper-amylasemia and hypertriglyceridemia during the acute phase, but without biliary tract disease or alcoholism. Acute pancreatitis usually occurred when serum triglyceride levels were above 1,000 mg/100 ml. In all patients during the acute phases, chylomicronemia and prebeta lipoproteinemia were present; serum cholesterol levels were normal or slightly elevated. Lipoprotein electrophoretic patterns were similar to the type V pattern described by Fredrickson. Serum lipids became normal in five patients given low fat diets (10 to 15 g/day), and they had no further abdominal pain; three others had satisfactory, but not complete remissions on diet therapy. Two others continued to have recurrent abdominal pain.It is concluded that the most consistent feature of one kind of pancreatitis is hyperlipoproteinemia with chylomicronemia. This condition probably occurs more frequently than has been previously recognized. Because of the favorable response to a low fat diet, this kind of pancreatitis can be treated adequately and further recurrence prevented.