Familial hyperalphalipoproteinemia.

A 26-member kindred had the newly recognized heritable hyperlipoproteinemia, familial hyperalphalipoproteinemia. In affected family members, hyperalphalipoproteinemia was not secondary to any diseases, drugs, or industrial exposures known to elevate alpha-lipoprotein (high-density) cholesterol (C-HDL) levels. Hyperalphalipoproteinemia was transmitted vertically through three generations. There were five matings of hyperalphalipoproteinemic to normal individuals, with 25 offspring. The ratio of offspring with elevated C-HDL levels to those with normal C-HDL levels was 12:13 (0.923), a ratio not significantly different from 1 (x2 equals 0.04), the ratio predicted for an autosomal dominant trait. In affected kindred members, levels of total plasma cholesterol were slightly elevated, those of low density lipoprotein cholesterol were normal to low, those of triglyceride were normal, and those of C-HDL were consistently elevated. Affected subjects were healthy, without xanthomata, and had no unique physical or neurological features.

Short term study of sucrose polyester a nonabsorbable fat-like material as a dietary agent for lowering plasma cholesterol.

The efficacy, safety, and acceptability of sucrose polyester (SPE), a fat-like material that is neither digested nor absorbed, were assessed in 13 normal and seven hypercholesterolemic subjects for its potential as a cholesterol-lowering agent. Addition or substitution of SPE for culinary fats in the diets of the normocholesterolemic individuals produced a mean reduction of total and low-density lipoprotein cholesterol of 14 and 17%, respectively (P less than 0.001), despite the daily ingestion of a diet containing 800 mg of cholesterol and of dietary fat with a P/S ratio of 0.4. Total and low-density lipoprotein cholesterol were not significantly reduced by similar 10-day feeding periods of SPE in seven subjects with familial hypercholesterolemia. High-density lipoprotein cholesterol and triglycerides were not changed in normal or hypercholesterolemic subject receiving SPE. Plasma vitamin A and E levels were reduced by 10 and 21% (p less than 0.02 and less than 0.001) in both normal and hypercholesterolemic subjects on SPE. These returned to the basal levels when SPE consumption was discontinued. SPE was recovered quantitatively (greater than 97%) in the stools, with the last measurable SPE being found day 3 to 5 after cessation of SPE intake. Despite recovery of 50 g or more of unhydrolyzed SPE in stools during SPE feeding, there was no clinical or chemical steatorrhea. On subtracting SPE's input to total stool fatty acids, it was found that "non-SPE" fatty acids in the stool had not increased during SPE feeding, SPE was easily incorporated into routine foodstuffs in addition to, or in substitution for, conventional dietary fats. On the basis of this short term evaluation in humans and other investigations with the rat and dog. SPE appears to have potential as a cholesterol-lowering agent.

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.

Maximal exercise stress testing in normal and hyperlipidemic children.

Electrocardiographic and cardiovascular responses during maximal exercise were evaluated in 103 normal children and in 82 children with familial hyperlipoproteinemia. The normal and hyperlipidemic children were comparable in regards to age, weight--height index, resting and exercise blood pressures, and maximal working capacity indices. The cohort of 82 hyperlipidemic children included 61 children (29 boys and 32 girls) with well defined "monogenic" familial hyperlipoproteinemia. Segmental ST depression on the exercise electrocardiogram occurred in 8 of these 29 boys (27.6%) as compared to 4 of 55 normal boys (7.3%), P less than 0.025 and in 6 of the 32 girls (19%) as compared to 7 of 48 normal girls (14.6%), P greater than 0.1. Segmental ST depression was present in 14 of 61 (23%) children with "monogenic" hyperlipoproteinemia, as compared to 11 of 103 (10.75%) normal (x2 = 4.47, P less than 0.05). An assessment of the clinical significance of an abnormal exercise electrocardiogram in male children with "monogenic" hyperlipoproteinemia must await the following: (1) two to four decades of observation and study of the development of morbid or mortal coronary disease, or (2) the future development of improved invasive or noninvasive techniques for the early detection of covert coronary occlusive disease. Currently, maximal exercise electrocardiography cannot be contemplated as a useful indicator of eventual premature coronary artery disease in asymptomatic hyperlipidemic children.

Composition of HDL-2 and HDL-3 in familial hyperalphalipoproteinemia.

The content and percent composition of cholesterol, triglyceride, phospholipids, and total proteins in HDL-2 and HDL-3 were quantitated in 5 women with familial hyperalphalipoproteinemia to determine if there are any distinctive characteristics of the high density lipoproteins in this heritable disorder. The 5 women with familial hyperalphalipoproteinemia (FHA) were compared to 4 normal women, with the groups being comparable in regards to age (40 +/- 3 and 37 +/- 5 years), total plasma cholesterol (202 +/- 9 and 188 +/- 16 mg/100 ml), triglyceride (75 +/- 12 and 95 +/- 19), and differing in levels of high density lipoprotein cholesterol (C-HDL, 84 +/- 6 and 61 +/- 3 mg/100 ml) respectively. Total cholesterol in the HDL-2 and HDL-3 fractions obtained by ultracentrifugation were 43.2 +/- 3.3 and 33.8 +/- 4.1 in FHA subjects, higher than total cholesterol in HDL-2 and HDL-3 in normals, 25.8 +/- 6.2 and 21.5 +/- 1.3 mg/100 ml, P less than 0.025. Total concentration of HDL-3 was higher in FHA than in normal subjects, respectively 222.4 +/- 22.6 and 149 +/- 7.2 mg/100 ml, P less than 0.025. Lipid-protein percent composition of HDL-2 and HDL-3 in FHA and normals was nearly identical, and polyacrylamide gel electrophoresis revealed no qualitative differences in band migration and appearance of the HDL-2 and HDL-3 fractions in normal and FHA subjects. In these women with FHA, there appears to be an increased concentration of normal HDL-2 and HDL-3.

Pediatric familial type II hyperlipoproteinemia: therapy with diet and colestipol resin.

Effects of a low-cholesterol, polyunsaturate-rich diet and a synthetic organic bile sequestrant polymer (U26,597A, colestipol) were studied in 21 children, heterozygous for familial hypercholesterolemia. Total cholesterol, beta-lipoprotein cholesterol, and triglyceride were measured twice on habitual diet, monthly for six months on a low-cholesterol diet, and monthly for six months on low-cholesterol diet plus 10 gm of colestipol per day. Total cholesterol (mean +/- 1 SD) was 295 +/- 37 on habitual diet, 278 +/- 29 on low-cholesterol diet, and fell significantly to 242 +/- 29 mg/100 ml on diet plus colestipol. Low-density lipoprotein (LDL) cholesterol was 234 +/- 37 on habitual diet, 220 +/- 28 on low-cholesterol diet, and fell significantly to 179 +/- 26 mg/100 ml on diet plus drug. Plasma triglyceride levels on habitual diet were 79 +/- 31, remained unchanged on low-cholesterol diet, 86 +/- 22, and were unaffected by low-cholesterol diet plus drug, 85 +/- 17 mg/100 ml. On diet alone, plasma LDL was not normalized (less than 170 mg/100 ml) in any of the 21 children, and cholesterol fell to within normal limits (less than 230 mg/100 ml) in only one child. The combination of diet plus colestipol resin normalized total and LDL cholesterol in 52% of the children. Cholesterol was lowered to a "moderately elevated" range of 230 to 250 mg/100 ml in an additional 14% of the children and LDL was lowered to a range of 170 to 190 mg/100 ml in an additional 29%. In 33% of the children, cholesterol remained greater than 250 mg/100 ml despite diet plus colestipol, while LDL was greater than 190 mg/100 ml in 19%. Colestipol is an effective and well-tolerated cholesterol lowering compound which, in conjunction with diet, may prove to be very useful in the treatment of children heterozygous for familial hypercholesterolemia.

Therapy of familial hypercholesterolemia in childhood: diet and cholestyramine resin for 24 to 36 months.

In 16 children heterozygous for familial hypercholesterolemia, two- to three-year therapy with diet and cholestyramine resin (16 gm/day) was assessed in terms of effectiveness, practicality, and safety. All 16 children had previously taken a low-cholesterol (less than 300 mg/day), polyunsaturate-rich (P/S ratio, 1.5:1) diet and choeltyramine resin (12 gm/day) for 12 months. In this study, the cholestyramine resin dose was increased to 16 gm/day, and follow-up was maintained through months 13 through 18, 19 through 24, 25 through 30, and 31 through 36. Eleven children had good drug adherence (four packs of cholestyramine per day) and five children had fair adherence (two to three packs per day). Plasma total cholesterol and low-density lipoprotein (LDL) cholesterol levels were not significantly lowered on the drug-plus-diet regimen as compared to diet alone in five children with fair drug adherence. For children with good drug adherence, mean plasma cholesterol level was lowered below levels achieved on diet alone by 13% (months 13 through 18), 12% (months 19 through 24), 12% (months 25 through 30), and 11% (months 31 through 36) (P less than .05). Reduction in plasma cholesterol level was no greater with 16 than with 12 gm of cholestyramine per day. There were no group changes in mean plasma triglyceride levels. Cholestyramine resin, when added to diet and maintained for two to three years effects a significant reduction in total and LDL cholesterol levels in about 60% of children heterozygous for familial hypercholesterolemia. Continued reinforcement of both diet and drug adherence is necessary in the face of gradual increments in plasma cholesterol level with time.

Plasma and dietary phytosterols in children.

Plasma phytosterol (plant sterol) levels were studied in 26 infants on various commercial formulas, in 36 infants on breast or cow's milk formulas, in 101 normal and 22 hypercholesterolemic children on a free diet, and in 32 hypercholesterolemic children on a low-cholesterol diet. Commercial formulas, poor in animal fats and enriched with vegetable oils, and low-cholesterol, phytosterol-rich diets generally elevated total plasma phytosterol levels in infants and hypercholesterolemic children from normal mean levels of 2 mg/100 ml to about 9 mg/100 ml. The implications of long-term three- to five-fold elevations of the plasma phytosterols (campesterol, stigmasterol, beta-sitosterol) in infancy and childhood are unknown. Watchful prospective analysis of plasma phytosterol levels may be useful, particularly in regards to otherwise unanticipated long-term effects of cholesterol-poor, phytosterol rich diets.

Effects of estrogenic compounds on triglyceride kinetics.

Paired studies of triglyceride kinetics were made in 8 women on and off postmenopausal estrogen supplementation. When estrogens were discontinued, mean very-low-density lipoprotein triglyceride (VLD-TG) and VLD-TG turnover rate fell respectively from 555 to 349 mg/100 ml, and from 30-18 mg/kg/hr (p smaller than 0.01). Maximal turnover rate (Vmax) and VLD-TG concentration at 1/2 V max (Km), were 82.4 mg/kg/hr and 704.14 mg/100 ml on estrogen and fell to 41.83 and 347.51 when estrogen was discontinued (p smaller than 0.01). Estrogen supplementation did not lengthen VLD-TG half-life or diminish the fractional turnover rate of VLD-TG. Estrogens apparently increase VLD-TG by augmenting VLD-TG production rates.

Effect of sex hormones on protamine inactivated and resistant postheparin plasma lipases.

Effects of estrogens and the synthetic anabolic-androgenic steroid, Oxandrolone, on extrahepatic (protamine inactivated) and hepatic (protamine resistant) lipases in postheparin plasma, were assessed in 15 subjects with familial hypertriglyceridemia. In six women receiving conjugated equine estrogen (1.25 mg/day), mean (+/- SE) postheparin protemine inactivated triglyceride lipase (PI-TGL) was depressed to 0.23 +/- 0.10 mumol FFA/ml/hr, and protamine resistant lipase was depressed to 5.3 +/- 0.5 mumol FFA/ml/hr. In the 2-wk period after estrogens were discontinued, PI-TGL remained depressed, 0.54 +/- 0.24, while PR-TGL increased to 7.3 +/- 0.88, p=less than 0.05. Mean triglycerides fell insignificantly from 628 +/- 136 to 447 +/- 44 mg/100 ml when estrogens were discontinued. There was no significant correlation between changes in PR-TGL and triglycerides when estrogens were stopped. In four women with familial hypertriglyceridemia, Oxandrolone significantly increased PR-TGL in two, increased PI-TGL in three, and reduced triglycerides in two. In five men with familial hypertriglyceridemia, Oxandrolone reduced triglycerides in four, increased PR-TGL in four, but had no effect on PI-TGL. For the nine hypertriglyceridemic subjects increments in PR-TGL failed to correlate significantly with decrements in triglyceride, (r=0.309, p is greater than 0.1). Selective alteration of PR-TGL and PI-TGL by estrogens and Oxandrolone may provide an approach to better understanding of the interaction of lipases and triglycerides in familial and acquired hypertriglyceridemia.

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.

Neonatal familial hypobeta-lipoproteinemia.

A kindred with four generation vertical transmission of familial hypobeta-lipoproteinemia was ascertained by measurement of low levels of cord blood low density lipoprotein cholesterol (C-LDL) in a propositus neonate. Measurement of cord blood C-LDL in conjunction with family studies allows the neonatal diagnosis of familial hypobetalipoproteinemia.

Familial hyper-alpha-lipoproteinemia: studies in eighteen kindreds.

A newly recognized familial hyperlipoproteinemia, familial hyper-alpha-lipoproteinemia, is described in 18 kindreds. Affected probands and relatives had distinctive elevations of alpha-lipoprotein cholesterol (C-HDL), slight elevations of total cholesterol, no elevation of LDL and VLDL cholesterol, and normal triglyceride levels. The proband and at least one additional first degree relative had distinctive elevations of C-HDL in 16 of 18 kindreds. Simple segregation analysis involving 84 offspring of 22 hyper-alpha X normal-alpha matings from these 16 kindreds revealed a ratio of hyper-alpha to normal of 37:47, a ratio not significantly different from 1:1 (chi 2(1) = 1.2), the ratio consistent with autosomal dominant transmission. Despite the suggestion of a major gene effect by this analysis, evaluation of the C-HDL distribution in kindred members failed to reveal bimodality, and familial correlation analysis revealed no parent-offspring correlation. The present data suggest that an environmental cause common to sibships is possibly important in causing the disorder. Longevity analysis demonstrated elongation of life expectancy for kindred members, and there was an apparent rarity of premature cardiac events.

Longevity syndromes: familial hypobeta and familial hyperalpha lipoproteinemia.

Longevity and morbidity and death from myocardial infarction were examined in eight kindreds with familial hypobeta lipoproteinemia and in 18 kindreds with familial hyperalpha lipoproteinemia. Expectation of life for males and females from kindreds with hypobeta lipoproteinemia was 9 and 12 years longer (p less than or equal to 0.002) than that indicated by population statistics for U.S. white populations, whereas expectation of life for males and females from kindreds with hyperalpha lipoproteinemia was 5 and 7 years longer (p less than 0.02). Morbidity from myocardial infarction in 115 living first-degree adult relatives of probands with hypobeta and hyperalpha lipoproteinemia and in 364 living first-degree adult relatives of normolipemic spouse controls were compared. Nonfatal myocardial infarction (MI) was reported for 18 of 364 (5 per cent) relatives of normal spouse controls and in 0 of 115 relatives of hypobeta and hyperalpha subjects (p less than 0.05). The ratios (mean+/-S.E.) of C-LDL to C-HDL in familial hypobeta and hyperalpha lipoproteinemia were 0.79+/-0.06 and 1.21+/-0.06, as compared to 2.41+/-0.12 in a control population (p less than 0.001). If high-density lipoproteins confer protection against development of atherosclerosis, whereas low-density lipoproteins have opposite effects, then we speculate that the low ratio of C-LDL:C-HDL may be related to prolonged longevity and decreased morbidity from myocardial infarction in familial hypobeta and hyperalpha lipoproteinemia.

Neonatal familial hypercholesterolemia.

Hypercholesterolemic and normal neonates from hypercholesterolemic kindreds were studied for 6 to 30 months. Sixteen of 22 hypercholesterolemic neonates and eight of 11 normal neonates came from families with "monogenic" hyperlipoproteinemia. At 6 or 12 months of age, plasma cholesterol level was greater than 200 mg/100 ml in eight of the 16 neonates with hypercholesterolemia. Four of these eight had cholesterol levels greater than or equal to 290 mg/100 ml at ages 6 to 18 months. On low cholesterol intake, at ages 6 to 12 months, five of seven infants with hypercholesterolemia had cholesterol levels less than 200 mg/100 ml. One of eight normal neonates from families with hypercholesterolemia had cholesterol levels greater than 200 mg/100 ml at ages 6 to 12 months. Neonatal diagnosis of familial hypercholesterolemia provides an opportunity for long-term primary prevention in a group at high genetic risk for premature is chemic heart disease.