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Objective: A novel method has been developed to study diurnal triglyceride (TG) profiles using repeated capillary self-measurements in an 'out-of-hospital' situation. We assessed the diurnal capillary TG (TGc) profile in males with mild obesity and evaluated the use of plasma and capillary TG as markers of insulin resistance., Design: Cross-sectional study., Setting and Subjects: Fifty-four lean (body mass index, BMI < 25 kg m-2) and 27 mildly obese (25 < BMI < 30 kg m-2), normolipidaemic males measured capillary TG concentrations on six fixed time-points over a 3-day period in an 'out-of-hospital' situation., Main Outcome Measures: The total area under the TGc curve (TGc-AUC) and incremental area under the TGc curve (TGc-IAUC) were used as estimation of diurnal triglyceridaemia. Fasting blood samples were obtained once. Food intake was recorded by all participants., Results: Obese and lean subjects had comparable fasting capillary TG concentrations (1.37 +/- 0.40 mmol L-1 and 1.32 +/- 0.53 mmol L-1, respectively). However, during the day, obese subjects showed a greater TG increase, resulting in significantly higher TGc-AUC (27.1 +/- 8.4 and 23.0 +/- 6.3 mmol h-1 l-1, respectively; P < 0.05) and TGc-IAUC (7.9 +/- 5.8 and 4.6 +/- 6.6 mmolh-1 L-1, respectively; P < 0.05). The total group of 81 males was divided into quartiles based on fasting plasma TG, fasting capillary TG, TGc-AUC and TGc-IAUC. Amongst these variables, TGc-AUC was the only significant discriminator of subjects with high homeostasis model assessment (HOMA) (insulin resistance) compared with low HOMA (insulin sensitive). Overall, BMI was the strongest determinant of HOMA., Conclusions: Diurnal TG profiles can be used to investigate postprandial lipaemia in both lean and mildly obese subjects and may help to detect subjects with an underlying disposition for hypertriglyceridaemia related to insulin resistance, i.e. the metabolic syndrome.

VLDL overproduction by enhanced hepatic FFA flux is a major characteristic of familial combined hyperlipidemia (FCHL). The postprandial complement component 3 (C3) response has been associated with impaired postprandial FFA metabolism in FCHL. We investigated the effects of 16 weeks of treatment with atorvastatin on postprandial C3 and lipid changes in 12 FCHL patients. Atorvastatin significantly lowered fasting plasma C3 and triglyceride (TG) in FCHL. Fasting TG and insulin sensitivity were the best predictors of fasting and postprandial C3. Postprandial triglyceridemia and C3 response, estimated as area under the curve (AUC), were significantly lowered by atorvastatin by 19% and 12%, respectively, albeit still elevated, compared with 10 matched controls. Postprandial FFA-AUC and postheparin plasma lipolytic activities remained unchanged after atorvastatin, suggesting no major effect on lipolysis. After atorvastatin, postprandial hydroxybutyric acid-AUC, which was elevated in untreated FCHL patients, was decreased, reaching values similar to those in controls. The present data show reduction of postprandial hepatic FFA flux in FCHL by atorvastatin, providing an additional mechanistic explanation for the reduction of VLDL secretion reported previously for atorvastatin. This was accompanied by a decrease in fasting plasma C3 concentrations and a blunted postprandial C3 response to an acute oral fat load.

Background: Increased triglycerides (TG) are associated with atherosclerosis. We determined free-living non-fasting TG concentrations in healthy Dutch subjects., Methods: Capillary TG (TGc) was self-measured by 109 males and 104 females during 3 days, on six fixed time-points each day; fasting, before and 3 h after lunch, before and 3 h after dinner and at bedtime. Daylong TGc-profiles were calculated as area under the mean TGc-curve (TGc-AUC). Reference values for "high" and "normal" daylong TGc concentrations were calculated as the 95th and 75th percentiles, respectively., Results: Fasting TGc were higher in males compared with females (1.41+/-0.75 versus 1.27+/-0.59 mmol/l), resulting in higher TGc-AUC (25.4+/-10.4 versus 20.6+/-9.8 mmol h/l). The highest TGc-concentrations were found in the evening. The majority of subjects (95%) had TGc during the evening below 4.6 mmol/l in males and below 3.7 mmol/l in females. Seventy-five percent of the subjects had TGc during the evening below 2.9 mmol/l in males and below 2.2 mmol/l in females. During the day (with exclusion of post-dinner TGc), 95% of the subjects had TGc below 3.7 mmol/l in males and below 3.6 mmol/l in females. Finally, 75% of the subjects had TGc during the day below 2.5 mmol/l in males and 1.7 mmol/l in females., Conclusions: The present data may help to delineate normal ranges of non-fasting TG and could be used to detect groups at risk for atherosclerosis on the basis of a disturbed TG metabolism.

FCHL (familial combined hyperlipidaemia) is the most frequent inherited disorder of lipid metabolism leading to premature atherosclerosis. The usual phenotype in FCHL is elevated fasting plasma triacylglycerols, low HDL (high-density lipoprotein)-cholesterol concentrations and elevated plasma apolipoprotein B concentrations. The metabolic basis for this phenotype is hepatic overproduction of VLDL (very-low-density lipoprotein), which is only partly linked to the insulin resistance associated with FCHL. At this stage the molecular basis for this VLDL overproduction is not known, but emerging evidence points to a disturbed trapping of peripheral fatty acids, resulting in enhanced hepatic flux of NEFA [non-esterified ('free') fatty acids]. Postprandial hyperlipidaemia with accumulation of lipoprotein remnants and NEFA have been implicated in the development of atherosclerosis in this disorder. It has been proposed that, by VLDL overproduction, fasting hypertriglyceridaemia may lead to 'overflow' of the catabolic cascade for triacylglycerol-rich particles, thereby explaining the delayed catabolism of remnants in FCHL. Delayed clearance of remnants of VLDL and chylomicrons leads to enhanced interaction of these highly atherogenic particles with the endothelium, and enhanced trans-endothelial migration of the particles, resulting in a chronic inflammatory response that is the initiation of the atherosclerotic lesion. In this process, activated leucocytes (either directly by the remnants or indirectly by released NEFA) play an important role by adherence to the endothelium and migration into the subendothelial space, where the uptake of atherogenic remnants results in a vicious cycle of activation of endothelium, leucocytes and production of cytokines.

Postprandial hypertriglyceridemia associated with insulin resistance is one of the cardiovascular risk factors in obesity and type 2 diabetes. It is not known whether diabetics have a more pronounced postprandial hypertriglyceridemia than obese subjects. Daylong triglyceridemia, representing postprandial lipemia, was determined in obese subjects with and without type 2 diabetes and in lean subjects. Nineteen type 2 diabetics (F/M: 7/12, body mass index [BMI]: 30.6 +/- 5.4 kg/m(2)), 45 obese nondiabetics (F/M: 16/29, BMI: 29.5 +/- 2.6 kg/m(2)) and 78 lean subjects (F/M: 28/50, BMI: 23.7 +/- 2.2 kg/m(2)) measured capillary triglycerides (TGc) during 3 days on 6 fixed time-points each day in an out-of-hospital situation. Daylong TGc profiles were calculated as mean integrated area under the TGc-curve (TGc-AUC). Fasting plasma TG were higher in diabetics and obese nondiabetics (1.81 +/- 0.79 and 1.77 +/- 0.80 mmol/L) compared with lean subjects (1.23 +/- 0.67 mmol/L, P <.001). TGc-AUC was similarly increased in both diabetics and obese nondiabetics (35.0 +/- 12.1 and 35.2 +/- 10.6 mmol.1 h/L) compared with lean controls (25.5 +/- 12.0 mmol.1 h/L, P <.001). Self-reported energy intake was not significantly different between the groups. Fasting TGc (r =.87, P <.001) and waist circumference (r =.51, P <.001) were the parameters best associated with TGc-AUC. Using stepwise multiple regression analysis, fasting TGc, BMI, total cholesterol, and high-density lipoprotein (HDL) cholesterol were the best predictors of TGc-AUC, explaining 77% of the variation. The cut-off level for "normal" TGc-AUC, calculated as the 75th percentile of TGc-AUC in lean subjects, was 30.7 mmol.1 h/L and corresponded with a fasting TGc of 1.8 mmol/L (eg, 1.6 mmol/L in plasma), calculated using univariate regression analysis. In conclusion, daylong triglyceridemia is similarly increased in diabetics and obese nondiabetics compared with lean subjects. Fasting TG and central obesity largely determine daylong triglyceridemia, independent of the presence of type 2 diabetes. Decreasing fasting plasma TG below 1.6 mmol/L could lead to a normalization of postprandial lipemia in obese subjects with and without diabetes.

Atherosclerosis is a low-grade inflammatory disease involving leukocytes, lipids, and glucose leading to endothelial dysfunction. Since activation of neutrophils by triglycerides and glucose has been described in vitro, we hypothesized that the postprandial phase is an inflammatory state affecting leukocytes, possibly contributing to endothelial dysfunction. We measured postprandial blood leukocyte counts, cytokines, hydroperoxides (HPOs), and flow-mediated vasodilation (FMD) in eight healthy males (age 23 +/- 2 years) after a FAT (50 g/m2) and GLUCOSE challenge (37.5 g/m2), a combination of both (MIXED test), and after WATER. All tests, except WATER, resulted in significantly impaired FMD (10% reduction) between t = 1 h and t = 3 h, accompanied by a significant increase of neutrophils (59% after FAT and 28% after GLUCOSE and MIXED), total plasma HPOs (15 to 31% increase), and plasma interleukin-8 (IL-8) (50-130% increase). WATER did not affect FMD, neutrophils, HPOs, or IL-8. Lymphocytes increased gradually in all tests (40-70% increase at t = 10 h compared with t = 0; P < 0.005), paralleling a gradual 3- to 5-fold interleukin-6 increase. Monocyte and erythrocyte counts did not change in any test. In conclusion, the neutrophil increment during postprandial lipemia and glycemia with concomitant IL-8 and HPO increases may contribute to endothelial dysfunction. Lymphocyte increment is a nonspecific diurnal process. Postprandial intravascular inflammatory changes may be relevant for the pathogenesis of atherosclerosis.

Background: The intra-individual variability of plasma lipids and apolipoproteins has not been studied systematically in familial combined hyperlipidemia (FCHL)., Methods: Intra-individual changes in fasting plasma lipids and apolipoproteins B and AI were determined in 18 untreated FCHL subjects and 16 unrelated, normolipidemic subjects. Participants were matched for gender, age and body mass index. The mean follow-up period of fasting plasma lipids was 48.91 +/- 35.46 (mean +/- S.D.) days. Postprandial lipemia was determined on 3 different days in 1 week in 90 healthy controls and 17 untreated FCHL subjects by the area under the diurnal capillary triglyceride curve (TGc-AUC)., Results: The coefficients of variation (CVs) for fasting plasma TG were similar between FCHL (23.2 +/- 10.2%) and controls (20.4 +/- 8.2%). The CVs for HDL-C, apo B and apo AI were the lowest of all fasting plasma measurements in both groups and there was no significant difference between FCHL (12.8 +/- 8.2%, 13.2 +/- 15.8% and 6.4 +/- 5.2%, respectively) and controls (11.4 +/- 4.3%, 11.3 +/- 10.6% and 7.8 +/- 4.6%, respectively). The CVs for postprandial lipemia were not different between FCHL (15.9 +/- 11.3%) and controls (15.1 +/- 11.0%), and were significantly lower than the CV of fasting capillary TG (TGc) in the same period (36.3 +/- 24.7% and 24.9 +/- 17.2%, respectively)., Conclusions: Our study does not provide evidence for short-term major changes in fasting or postprandial lipemia or apolipoproteins in FCHL when systematically compared to healthy controls., (Copyright 2002 Elsevier Science B.V.)

Free fatty acids (FFAs) are involved in the transportation of energy; in the postprandial phase to the peripheral tissues and in the postabsorptive phase from the adipose tissue to the liver. In the postprandial phase, FFAs are mainly derived from hydrolysis of triglyceride-rich particles like chylomicrons and very low-density lipoproteins (VLDL). The flux of FFAs is directed to peripheral cells such as adipocytes and muscle cells. In the postabsorptive period, FFAs are transported to the liver after being released from intracellular storage in the adipocytes. Complement component 3 (C3) plays an important role in the uptake of free fatty acids by the peripheral cells and their esterification to triglycerides. Since C3 is also involved in the pathogenesis of the insulin resistance syndrome, and since a deviant FFA metabolism with an increased FFA flux to the liver may induce insulin resistance, it is hypothesized that C3 may form the missing link between FFA metabolism and insulin resistance. In addition, recent studies have increasingly indicated that atherosclerosis is in fact an inflammation-based process involving complement-dependent responses, in which FFAs seem to play a role in the complement-dependent pathway. It has recently become apparent that FFAs have a regulatory function in the transcription of DNA, in relation to lipoprotein metabolism. This is where PPAR-gamma and PPAR-alpha agonists ('glitazones' and fibrates respectively) are active (PPAR is an abbreviation for peroxisome proliferation activating receptor). Glitazons may play an important role in the treatment of insulin resistance and related disorders. Acquiring more knowledge about the relationship between complement and FFA metabolism may increase our understanding of these processes and provide openings for the development of new antiatherogenic strategies.

Plasma concentrations of the third complement component (C3) predict the risk of myocardial infarction. Because chylomicrons stimulate C3 production by adipocytes in vitro, we investigated plasma C3 changes in vivo after an oral fat load. Thirty-seven subjects (20 normolipidemic patients with coronary artery disease [CAD] and 17 healthy control subjects) underwent an oral fat load (50 g/m(2)). C3 was measured at baseline and at 2-hour intervals after fat intake for 10 hours. The effects of lipid lowering by simvastatin were evaluated in 16 patients. Fasting plasma C3 was 1.06+/-0.26 and 0.90+/-0.12 g/L in CAD patients and control subjects, respectively. Fasting C3 was correlated with several parameters associated with insulin resistance. The best determinant of fasting C3 was waist circumference (adjusted R(2)=0.48, beta=0.71, P<0.001); the addition of postprandial triglyceridemia to the model improved it (adjusted R(2)=0.63). Plasma C3 levels at 2, 4, and 6 hours after fat ingestion were significantly higher than fasting levels in patients and control subjects. C3 increased maximally to 1.39+/-0.33 g/L in patients and to 1.11+/-0.18 g/L in control subjects (P<0.01 for patients versus control subjects). Total postprandial triglyceridemia was the best determinant of maximal C3 increase (adjusted R(2)=0.47, beta=0.70; P<0.001). Treatment with simvastatin decreased fasting and postprandial C3 by 6% and 39%, respectively (P<0.05 for both versus no treatment). Postprandial plasma C3 concentrations increase in CAD patients and control subjects. Fasting C3 is associated with waist circumference, but postprandial C3 increment is associated with postprandial lipemia. Fasting and postprandial C3 concentrations decrease after treatment with simvastatin.

The socio-economic impact of obesity, one of the most prevalent medical disorders in Western society, is mainly due to its association with a higher risk of coronary heart disease. It is likely that atherosclerosis develops against a background of obesity as a result of the insulin resistance that is invariably present in overweight and obese subjects. Fasting plasma lipids may be normal in obese subjects, but they are usually affected by postprandial hyperlipidemia, which is probably due to competition between chylomicrons and VLDL for the same metabolic pathways. The basis for the impaired clearance of atherogenic chylomicron remnants is the fact that obesity causes hepatic apo B-VLDL overproduction, and thus leads to competition with chylomicrons and their remnants at the lipolytic pathway (lipoprotein lipase and hepatic lipase) and receptor level (LDL-receptor and remnant-receptor). The overproduction of VLDL is probably caused by an enhanced hepatic flux of free fatty acids in both the postprandial (from the lipolysis of triglyceride rich particles) and postabsorptive states (from adipocytes). Weight reduction by means of life-style changes, supported by medical interventions with inhibitors of intestinal fat absorption (e.g. Orlistat) or appetite suppressants (e.g. Sibutramine), is essential in order to decrease the risk of atherosclerosis. Furthermore, improvement of risk factors can be achieved by means of fibrate treatment to modulate fasting and postprandial triglyceride levels. Treatment with cholesterol synthesis inhibitors ("statins") may reduce hepatic VLDL production and increase the clearance of atherogenic remnants by upregulating LDL-receptors, thus leading to improved fasting lipid levels and enhanced clearance of chylomicron remnants. Finally, the use of thiazolidinedione derivatives to improve insulin sensitivity may be one of the options for reducing the risk of atherosclerosis in obese subjects.

Fasting plasma triglycerides (TG) show a high intra-individual variability, and therefore, repeated measurements and alternative methodology are necessary when studying TG metabolism. In search for novel approaches to study TG changes, we evaluated the feasibility of determining ambulatory capillary TG. In addition, well-known characteristics (e.g. gender differences) of TG metabolism in healthy subjects were determined. In 18 subjects with a wide range of fasting plasma TG, the results of standardised oral fat loading tests (50 g m(-2)) were compared to their diurnal capillary TG profiles, measured on 3 different days, six times each day in an out-patient clinic setting. The diurnal TG-profile was calculated as area under the capillary TG curve (TGc-AUC) and as incremental area (dTGc-AUC). Clearance of plasma TG after the acute oral fat load correlated well with the diurnal TGc-AUC (r=0.77; P<0.01). In addition, hypertriglyceridemic subjects (plasma TG >2.0 mmol l(-1)) had a higher diurnal triglyceridemia (49.83+/-15.37 h mmol l(-1)) as well as a higher response of plasma TG to the oral fat load (42.10+/-15.37 h mmol l(-1)), than the subjects with normal fasting plasma TG (29.83+/-11.75 h mmol l(-1) (P<0.05) and 20.75+/-5.89 h mmol l(-1) (P<0.01), respectively). In an observational study, 106 volunteers (54 females and 52 males) measured capillary triglycerides. Food intake was recorded and fasting blood was drawn once at the start of the study. Body composition was assessed by anthropometric parameters and body-impedance. Repeated measurements of diurnal triglyceridemia tended to be less variable than fasting capillary triglycerides (mean coefficients of variation 15.1% (range: 0.60-45.9%) and 24.9% (range: 1.44-72.7%), respectively; P=0.09) for the whole group and in males (18.6% (0.60-45.9%) and 24.0% (1.4-58.2%), respectively; P=0.07). The mean diurnal TGc-AUC and dTGc-AUC were lower in females (16.50+/-4.85 and 1.82+/-3.46 h mmol l(-1), respectively) than in males (23.44+/-6.50 and 6.93+/-4.67 h mmol l(-1); P<0.001 for each). The total daily energy intake was lower in females (8911+/-1905 kJ) than in males (11042+/-2604 kJ, P<0.001) because of a lower intake of all nutrients. In females, estrogen status determined significantly the capillary TG profiles. Stepwise multiple regression analysis for females and males, with TGc-AUC as the dependent variable, showed that the best predictors were fasting capillary TG, gender, systolic blood pressure and mean daily energy intake, explaining 72% of the variation. Incremental triglyceridemia was best described by gender, mean daily protein intake and systolic blood pressure, explaining 42% of the variation. Diurnal capillary TG profiles may be used to estimate the total daily load of potential atherogenic particles to which individuals are subjected during the day without the need for metabolic ward studies.

Background: Elevated fasting and postprandial triglycerides (TG) are established risk factors for Coronary Heart Disease (CHD). Usually, fasting plasma TG are measured, although TG are mainly produced in a postprandial state. Our objective was to investigate diurnal TG profiles using serial capillary TG measurements, in normolipidemic healthy males., Materials and Methods: Forty-eight, non-obese, non-smoking males (range: 20-55 years, mean age: 32 +/- 12 years), measured diurnal capillary TG, at six fixed timepoints during the day on three different days and recorded their food intake. Insulin sensitivity was estimated by HOMA. Diurnal capillary TG profiles were calculated as integrated area under the mean capillary TG curve (TGc-AUC)., Results: All subjects had normal fasting plasma TG and cholesterol. The average TGc-AUC was 23.6 +/- 6.7 mmol h L-1. Significant correlations with TGc-AUC were: fasting insulin (r = 0. 40, P < 0.005), HOMA (r = 0.32, P < 0.05), relative fat mass (r = 0. 31, P < 0.05), dietary protein-(r = 0.31, P < 0.05) and saturated fat intake (r = 0.30, P < 0.05). Age was not associated to diurnal triglyceridemia. After subdividing the group into quartiles on the base of TGc-AUC, differences were found between the highest (n = 12) and lowest quartile (n = 12) for: fasting capillary TG, fasting insulin, HOMA and systolic blood pressure. Fasting plasma TG and dietary intake were not different., Conclusion: Diurnal TG profiles in healthy normolipidemic males are not age-dependent, but are associated to insulin sensitivity, fat mass and diet. Diurnal capillary TG profiles may be a valuable additional tool in estimating a risk profile for CHD since significant differences in diurnal TG are not always reflected by elevated fasting plasma TG.

Objective: To study predictors of diurnal capillary triglyceride (TG-c) profiles in healthy males., Design: Observational, cross-sectional., Setting: University Hospital Utrecht, Department of Internal Medicine, the Netherlands., Method: In 30 healthy males (20-34 years) TG-c was measured during three days, six times a day. Fasting blood was collected at inclusion. Body composition and HOMA ratio as insulin sensitivity index were determined. TG-c profiles were calculated as integrated area under the mean TG-c curve (TG-AUC)., Results: All subjects had normal fasting plasma and capillary TG and cholesterol concentrations. Diurnal TG-c values were higher than fasting values. The average TG-AUC was 24.6 +/- 6.7 mmol/l over 14 hrs. Variables associated with TG-AUC were: fasting TG-c, relative fat mass, total protein and saturated fat intake. After correction for fasting TG-c only diet and fat mass were correlated with TG-AUC. The relative fat mass was positively correlated with the HOMA ratio and fasting insulin concentrations, suggesting that decreased insulin sensitivity accompanied increased body fat., Conclusion: Triglyceride profiles provide information about the total diurnal TG load. The best determinant of diurnal triglyceride changes was fasting triglycerides. However, diet, body composition and insulin sensitivity are also important. Future investigations should address the question whether triglyceride profiles may be used to estimate more accurately the individual risk profile for coronary heart disease.

A patient with neurofibromatosis type 1 and watery diarrhoea syndrome due to a VIP-producing adrenal phaeochromocytoma (Case Report). J Intern Med 1999; 246: 231-234. A 43-year-old patient with neurofibromatosis type 1 suffered from watery diarrhoea syndrome induced by excessive production of vasoactive intestinal polypeptide (VIP) in an adrenal phaeochromocytoma. This case report emphasizes that patients with neurofibromatosis are prone to develop more than one disease induced by tumours originating from the neural crest. Since excessive VIP production in a phaeochromocytoma may mask the symptoms of catecholamine overproduction, and in view of the therapeutic consequences, neurofibromatosis patients with hyperVIP-aemia must be checked for the presence of a phaeochromocytoma.

A non smoking male patient 42 years old complained of pain in the calves after exercise and had a low 'high density'-lipoprotein (HDL) cholesterol serum concentration. Angiography of the leg vessels revealed no abnormalities. Treatment with simvastatin and gemfibrozil did not affect HDL cholesterol concentrations. Blood tests of relatives made familial hypo-alpha-lipoproteinaemia unlikely. It appeared that the patient had used anabolic steroids; these increase hepatic lipase activity leading to a higher metabolism of HDL and reduced HDL cholesterol levels.

The role of the lipoprotein lipase (LPL) gene in familial combined hyperlipidaemia (FCH) is unclear at present. We screened a group of 28 probands with familial combined hyperlipidaemia and a group of 91 population controls for two LPL gene mutations, D9N and N291S. LPL-D9N was found in two probands and one normolipidaemic population control. LPL-N291S was found in four probands and four population controls. Subsequently, two pedigrees from probands with the D9N mutation and two pedigrees from probands with the N291S mutation were studied, representing a total of 24 subjects. Both LPL gene mutations were associated with a significant effect on plasma lipids and apolipoproteins. Presence of the D9N mutation (n = 7) was associated with hypertriglyceridaemia [2.69 +/- 1.43 (SD) mmol L-1] and reduced plasma high-density lipoprotein cholesterol (HDL-C) concentrations (0.92 +/- 0.21 mmol L-1) compared with 11 non-carriers (triglyceride 1.75 +/- 0.64 mmol L-1; HDL-C 1.23 +/- 0.30 mmol L-1, P = 0.03 and P = 0.025 respectively). LPL-D9N carriers had higher diastolic blood pressures than non-carriers. LPL-N291S carriers (n = 6) showed significantly higher (26%) apo B plasma concentrations (174 +/- 26 mg dL-1) than non-carriers (138 +/- 26 mg dL-1; P = 0.023), with normal post-heparin plasma LPL activities. Linkage analysis revealed no significant relationship between the D9N or N291S LPL gene mutations and the FCH phenotype (hypertriglyceridaemia, hypercholesterolaemia or increased apo B concentrations). It is concluded that the LPL gene did not represent the major single gene causing familial combined hyperlipidaemia in the four pedigrees studied, but that the LPL-D9N and LPL-N291S mutations had significant additional effects on lipid and apolipoprotein phenotype.

Hepatic VLDL overproduction in familial combined hyperlipidaemia (FCH) may delay the clearance of atherogenic apolipoprotein (apo) B containing particles. We investigated if normalization of fasting plasma triglycerides (TG) by hypolipidaemic treatment results in improved metabolism of apo B48 and apo B100 in six male subjects with FCH and compared them to six normolipidaemic controls. The FCH patients were studied before (TG, 5.2 +/- 1.2 mmol l-1; mean +/- SEM) and after therapy (TG, 2.1 +/- 0.3 mmol l-1) with either simvastatin (n = 4) or combined therapy with gemfibrozil (n = 2). The postprandial changes of apo B100 and apo B48 were studied after a single oral fat meal (24 h; 50 gram fat m-2). Changes in triglyceride rich particles (TRP; d < 1.006 g ml-1) and remnant fractions (REM; d:1.006-1.019 g ml-1) of apo B were quantitated by scanning silverstained SDS-PAGE (4-15%). Apo B48 in fasting TRP in untreated and treated FCH was 15% and 14% of total apo B, and 6% in controls (P < 0.05). In controls, postprandial B48 increased maximally at 4 h by 81% in TRP and by 137% in REM compared to baseline. In treated FCH, the postprandial apo B48 pattern normalized in TRP compared to the untreated state. Postprandial apo B100 in controls decreased in TRP and REM by 33% and 18% (P < 0.05). In untreated and treated FCH, postprandial apo B100 remained unchanged vs. baseline in TRP and in REM suggesting hypersecretion of VLDL. The elimination of B100--assessed as area under the curve--in TRP (32.5 +/- 3.6 au.h; mean +/- SEM) and REM fractions (33.2 +/- 3.1 au.h), improved significantly after treatment (21.0 +/- 2.8 and 20.4 +/- 3.3 au.h, respectively). The apo B48 clearance in TRP fractions was improved after treatment (4.3 +/- 1.4 au.h vs. 2.9 +/- 1.2 au.h; P = 0.06), but not in REM fractions (2.8 +/- 1.0 au.h vs. 1.8 +/- 0.5 au.h; NS). In conclusion, in FCH subjects with apo B100 hypersecretion and increased fasting plasma apo B48 levels, reduction of fasting plasma TG improved, but did not normalize, TRP apo B48 and B100 metabolism. However, therapy normalized postprandial apo B100 remnant metabolism. Impaired postprandial apo B metabolism may be instrumental in the development of premature atherosclerosis in FCH subjects.

The effect of tetrahydrolipstatin (THL), a recently developed pancreatic lipase inhibitor, on fasting plasma lipid levels and postprandial lipoprotein and retinyl palmitate (RP) metabolism was studied in 17 hyperlipidemic subjects, using an oral RP fat load (8 hours, 50 g fat/m2). During therapy with THL, fasting plasma cholesterol, low-density lipoprotein (LDL) cholesterol, and apolipoprotein (apo) B concentrations decreased by 8% (P = .006), 9% (P = .002), and 10% (P = .002), respectively. The postprandial plasma triglyceridemia, which was expressed as the area under the 8-hour triglyceride (TG) curve, improved by 27% during THL therapy (P = .04) without changes in fasting plasma TG or high-density lipoprotein (HDL) cholesterol levels. The improved postprandial triglyceridemia was accompanied by a 19% reduction in circulating levels of chylomicrons and chylomicron remnants, determined by the decreased areas under the 8-hour RP curves. The most likely mechanisms involved are decreased formation of chylomicrons by a decrease of intestinal TG absorption as a consequence of THL treatment, as well as reduced delivery of dietary lipid and fatty acids to the liver and subsequent upregulation of hepatic LDL receptors. In agreement with the latter mechanism, the decrease in postprandial lipemia expressed as delta area under the TG curve was significantly related to the decrease (delta) in LDL cholesterol level during THL treatment (r = .81, P = .0001). The present data indicated that pancreatic lipase inhibition improved postprandial lipoprotein metabolism, which in turn resulted in lower plasma total and LDL cholesterol concentrations.

The relationship between lipoprotein(a) [Lp(a)] and metabolism of triglyceride-rich lipoproteins (TRL) was studied in 58 untreated patients with familial combined hyperlipidemia (FCH) from eight different kindreds, 17 spouse controls, and 17 unrelated controls. Lp(a) plasma concentrations were not significantly different between FCH subjects (343 +/- 61 mg/L, mean +/- SEM) and controls (249 +/- 52 mg/L). In FCH, log-transformed Lp(a) levels correlated positively with postheparin lipoprotein lipase ([LPL] r = .61, P = .0002) and hepatic lipase ([HL] r = .46, P = .008) activities and total plasma cholesterol level (r = .30, P = .03). In controls, Lp(a) correlated with LPL (r = .50, P = .04) and total plasma cholesterol level (r = .51, P = .003). In eight FCH patients, treatment with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin resulted in significantly increased mean LPL activities and plasma Lp(a) concentrations. In three of these FCH patients, repeated measurements during 1 year demonstrated that changes in Lp(a) concentrations were paralleled by similar changes in LPL activity, but not HL activity. The observed correlation between postheparin plasma lipolytic activities and Lp(a) plasma concentrations suggests a connection between the metabolism of TRL and Lp(a).

The treatment with desmopressin prior to surgery of patients with mild haemophilia A (HA) and Von Willebrand's disease (VWD) was retrospectively evaluated in a general hospital, from 1978 until 1987. From a group of 87 treated patients, 40 patients are reported (21 VWD, 19 HA) of which plasma factor VIII (FVIII) and Von Willebrand factor (VWF) concentrations were determined before, and twice after desmopressin treatment. Desmopressin was administered intravenously at a dose of 0.4 micrograms/kg body weight. Tranexamic acid was used only when surgery in the mouth cavity was performed, at a dose of 1 gram three times a day. Side effects were seen only in 5 patients (3 VWD, 2 HA). No significant difference between both groups was seen in bleeding tendency, transfusion necessity and side effects (chi 2 test). In both groups, FVIII and VWF concentrations increased significantly after 20 and 60 minutes following DDAVP administration (paired t-test). After 360 minutes, the FVIII concentration increased significantly in both groups, however, only in the VWD patients did VWF increase significantly. In neither group did initial FVIII concentrations correlate with the increase in FVIII (linear regression analysis). One female patient reacted differently to DDAVP, with a decrease in FVIII and VWF values. Desmopressin is a safe and effective agent in the management and prophylaxis of bleeding tendency in patients with mild HA and mild VWD.