JCL Roundtable: health information technology in the management of lipoprotein disorders.

One of the most serious challenges to all physicians is the maintenance of therapy for those chronic disorders that at present cannot be cured. Elevations of low-density lipoprotein and very low-density lipoprotein are among the most common of those disorders. We are now in an era in which 2 fundamental developments of modern technology have come together. These are the supply of effective and safe lipid-lowering drugs as well as the ability to closely monitor pertinent measures in our patients. The rapid conversion of our health care systems into large teams of professionals with direct support from third-party payers has made it possible to coordinate chronic care through electronic medical records and electronic communication. As a result, with effective planning and organization, we can guide our patients toward better adherence to successful medical regimens. These issues are evolving rapidly and have been presented in some detail in the December 2013 issue of the Journal. I was joined in this Roundtable discussion by 3 health professionals who have had extensive experience with the application of health information technology. They are Dr. Karen Aspry and Dr. Alan Brown, both clinical cardiologists, and Dr. Matthew Ito, a Doctor of Pharmacy.

Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia.

Stearoyl-CoA desaturase (SCD) is expressed at high levels in several human tissues and is required for the biosynthesis of oleate (18:1) and palmitoleate (16:1). These monounsaturated fatty acids are the major components of phospholipids, triglycerides, wax esters, and cholesterol esters. Mice with a targeted disruption of the SCD1 gene have very low levels of VLDL and impaired triglyceride and cholesterol ester biosynthesis. In the HYPLIP mouse, a model of hyperlipidemia, there was a 4-fold increase in hepatic SCD activity, a 1.8-fold increase in the desaturation index, and a 2-fold increase in plasma triglycerides. We used the plasma ratio of 18:1/18:0 (the "desaturation index") as an in vivo measure of SCD activity in human subjects. In human subjects with triglycerides ranging from 0.3 to 20 mM, the desaturation ratio accounted for one-third of the variance in plasma triglyceride levels. A 2-fold increase in the desaturation index was associated with a 4-fold increase in plasma triglycerides. In human subjects exposed to a high carbohydrate diet, the desaturation index explained 44% of the variance in triglycerides. We propose that many of the factors that influence plasma triglyceride levels do so by converging upon the regulation of SCD activity.

The double pre-beta very low density lipoprotein lipoproteinemia (DPBL): a new dyslipoproteinemic state.

A new dyslipoproteinemic state, characterized by two populations of very low density lipoprotein particles giving the electrophoretic appearance of two pre-beta bands, the double pre-beta lipoproteinemia, is described. Based upon the lipid and apoprotein composition, it can be inferred that the slow moving pre-beta component is probably made up of remnant very low density lipoprotein particles; the absence of apo B 48 in the very low density lipoprotein fraction in these subjects rules out the intestinal origin of this remnant. Clinical interest in the double pre-beta lipoproteinemia relates to its potential atherogenicity; in fact it seems to be causally associated with such pathological conditions as hypothyroidism, uremia and dialysis, which are frequently accompanied by clinical complications of atherosclerosis. Double pre-beta lipoproteinemia also shows familial aggregation. Six years follow-up in a large family kindred has demonstrated that the family members carrying the double pre-beta lipoproteinemia, develop an incidence of coronary and cerebrovascular events higher than that of family members without the double pre-beta lipoproteinemia.

Transient lipoprotein deficiency at birth: a cause of low levels of vitamin E in the newborn.

In newborns, the level of vitamin E in blood is very low as compared to that of placental intervillous blood and maternal blood. In our attempt to investigate the role of placenta in the transfer of vitamin E from the maternal to the newborn circulation, we have discovered that vitamin E is able to enter placental blood but is not being efficiently transferred from the placental to the newborn circulation. It appears from our preliminary study that the most limiting factor in the transfer of vitamin E from the placental to the newborn circulation is the transient deficiency of prebeta lipoprotein in the newborn blood at birth. A transient lipoprotein deficiency is implicated as a cause of low levels of vitamin E in the newborn.

Type III hyperlipoproteinemia associated with apolipoprotein E deficiency.

Subjects with type III hyperlipoproteinemia develop premature atherosclerosis and have hyperlipidemia due to an increase in cholesterol-rich very low density lipoproteins (VLDL) of abnormal electrophoretic mobility. Apolipoprotein E is a major protein constituent of VLDL and appears to be important for the hepatic uptake of triglyceride-rich lipoproteins. A new kindred of patients with type III hyperlipoproteinemia is described in which no plasma apolipoprotein E could be detected, consistent with the concept that type III hyperlipoproteinemia may be due to an absence or striking deficiency of apolipoprotein E.

Normotriglyceridemic abetalipoproteinemia. absence of the B-100 apolipoprotein.

In the two genetic forms of abetalipoproteinemia described previously, recessive abetalipoproteinemia and homozygous hypobetalipoproteinemia, all lipoproteins that normally contain apolipoprotein B are absent from plasma. We describe here a new disorder in which normal low density and very low density lipoproteins are absent, but in which triglycerides are absorbed from the intestine and chylomicrons are present in plasma. The underlying molecular defect appears to be selective deletion of the hepatogenous B-100 apolipoprotein. The B-48 apolipoprotein found in chylomicrons is spared. These findings suggest that the two species of apolipoprotein B are under separate genetic control and that low density lipoproteins are not normally derived from chylomicrons.

Inability of serum from abetalipoproteinemic subjects to stimulate proliferation of human smooth muscle cells and dermal fibroblasts in vitro.

Serum from two patients with abetalipoproteinemia, a rare disorder of lipid metabolism characterized by the absence of chylomicrons and very low density and low density lipoproteins, did not stimulate the proliferation and growth of human smooth muscle cells or dermal fibroblasts in vitro as effectively as normal serum. The growth-promoting activity of this serum was comparable to that observed for lipoprotein-deficient plasma from normolipidemic subjects. Although the mitogenic effect of abetalipoproteinemic serum was improved with supplementation of low density lipoproteins, it was still about half the activity achieved with normal serum. However, the growth-promoting activity of this serum was completely restored to normal levels after addition of a lysate of normal platelets. In contrast, the mitogenic activity of lipoprotein-deficient plasma remained unchanged after addition of a lysate from abetalipoproteinemic platelets, whereas a similar supplementation of normal platelets completely restored its growth-promoting activity to normal. Thus, the inability of abetalipoproteinemic serum to promote growth appears to be due both to a deficiency of a platelet-releasable growth factor(s) and to the absence of serum lipoproteins.

Lipid deficiencies, leukocytosis, brittle skin--a lethal syndrome caused by a recessive mutation, edematous (oed), in the mouse.

A new neonatal lethal mutation in the mouse with pleiotropic effects, edematous (oed), arose spontaneoutosomal recessive mode of inheritance. The external phenotypic characteristics include a generally bloated appearance, shiny celophane-like skin, and distal hematomata of the extremities. Internally, no gross or histological abnormalities could be identified, with the exception of a striking leukocytosis. Biochemical analysis revealed a severe disturbance of lipid metabolism. Deficiencies in the VLDL, LDL, and the HDL lipoprotein fractions have been found in the mutant plasma. In addition, all serum lipids are markedly decreased. However, in the mutant liver, only triglycerides are significantly decreased; total liver cholesterol and phospholipid values are within normal limits. The primary biochemical defect as well as the causal relationship between the striking abnormalities of lipid metabolism and those of skin and blood are unknown at this time.