Plant stanol and sterol esters in familial hypercholesterolemia

The Journal of LABORATORY and CLINICAL MEDICINE Copyright © 2004 by Elsevier Inc.

VOLUME 143

APRIL 2004

NUMBER 4

THIS MONTH IN J Lab Clin Med Issue Highlights for April 2004

Plant stanol and sterol esters in familial hypercholesterolemia As early as 1953, it was observed that plant compounds resembling cholesterol could influence lipid absorption and plasma lipid levels, and could prevent the experimental atherosclerosis produced by cholesterol feeding in rabbits. These compounds have not come into wide clinical use for a variety of reasons, including the relative inconvenience of use (incorporating them into a margarine-like spread is one delivery tactic); there’s also little incentive to do major clinical trials for a product that might prove neither patentable nor profitable. Nonetheless, these substances are interesting for what they can teach us about lipid homoestasis; they may be part of the benefit of a vegetarian diet, and there may be cases uniquely appropriate for their use. In this month’s issue of the Journal, Dr Anna Ketoma¨ki and her colleagues from the Universities of Helsinki and Kuopio, Finland, report the use of plant stanol and sterol esters to lower plasma lipid levels in members of a family with hypercholesterolemia. As described beginning on page 255, the parents were each heterozygous for a mutation of the LDL receptor gene (FH-Helsinki in one and FH-North-Karelia in the other), and the adult child inherited both mutations. The child was severely affected, having been diagnosed in infancy; ileal bypass and portacaval shunt were performed early in childhood, and aortic and coronary surgery was nonetheless required at age 25 because of atheromatous disease. Lipopheresis (using a dextran adsorptive column, treating four liters of plasma at intervals of 2-4 weeks) and an HMG-CoA-reductase inhibitor were the principal therapies in use at the time of the study. The parents had tendon xanthomata without recognized arterial disease, and had declined drug therapy. The parents both had modestly increased total serum cholesterol levels, and the more severely affected child was controlled to a similar value by the therapy being given. There were differences, however, if one measured selectively the sterols that reflected lipid absorption (such as campesterol) or those that were the result of synthesis (e.g., lathosterol). The former were far higher—as much as tenfold—in the child than they were in the parents, while the latter were only marginally increased. In the child’s plasma, higher proportions of squalene (70% vs 60%) and non-cholesterol sterols (⬃90% vs ⬃70%) were carried in the LDL fraction than was the case for the parents. The three subjects were given spreads containing sterol esters or stanol esters, and were to use them at the rate of 25 g/day. The parents were re-studied after four weeks on the spreads; each was studied on each spread (blinded, random order). The child took longer to reach equilibrium— presumably because of the treatment, which was continued—so the study diet intervals were longer. J Lab Clin Med 2004;143:195-8. © 2004 Elsevier Inc. All rights reserved. 0022-2143/$ – see front matter doi:10.1016/j.lab.2004.02.003

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J Lab Clin Med April 2004

Each spread reduced serum total cholesterol about 14% in the heterozygous parents and by about 9% in the child. Consumption of the sterol ester spread increased serum plant sterol concentrations; for example, campesterol rose in the child’s serum from 5 to 9 mg/dL. The ratios of plant sterols to cholesterol also went up. Consumption of the stanol ester spread had the opposite effect, however. This adds a note of uncertainty to a story that had already led to booming sales of plant ester spreads in “health food” stores. That is, one can indeed lower cholesterol modestly through the use of such products, but there can also be an associated rise in the plasma levels of plant sterols—the effect is not entirely the result of inhibiting the absorption of cholesterol and related compounds. Whether this associated rise in plant sterols is a good thing or a bad thing remains to be seen.

Permeability-enhancing factors in focal sclerosing glomerulonephritis (FSGN) In 1986, Weiss and co-workers described a new histologic variant of focal segmental glomerulosclerosis; it had particularly severe proteinuria, and ran a fulminant course to early renal failure. They termed it “collapsing” FSGN, and the name has stuck. It did not seem to have any behavioral or infectious risk factors, but it occurred disproportionately in black patients. It is being recognized more frequently, and there is concern that its actual incidence is also rising. A study reported in this month’s issue addresses the severity of proteinuria in this disorder. Dr Ellen McCarthy and her co-authors from the Medical College of Wisconsin and the University of North Carolina examined the ability of plasma from this disorder to influence the permeability of isolated rat glomeruli. Serum from each of eleven patients was incubated briefly with glomeruli, some with or without normal serum. The albumin permeability was then assessed by recording the change in glomerular volume in response to changes in the albumin concentration in the bath. As expected from earlier work, ten of the eleven test sera led to an increased albumin permeability. Several of the test samples were small reserved aliquots; for five, there was enough to repeat the study in the presence of added normal serum. In each of those cases, the permeability changes were largely prevented by the presence of normal serum. In the more usual form of FSGN, one may also observe such an enhancement of glomerular permeability, and it has been attributed to a small protein present in the patients’ plasma. It’s not yet clear whether the substance is the same in the “collapsing” variant, but it seems likely. The inhibition of its effect by normal plasma also remains to be explored; it may mean that the substance is a normal component of plasma that is inactivated and cleared by a binding protein The paper may be found on page 225.

From pluri- to omni-: How potent are our stem cells? Stem cells have always been interesting, but they have received a great deal of attention in the last few years. As more has been learned about differentiation, de-differentiation, and the retention of small populations of more primitive cells in what seem to be mature organs, there has been a lot of excitement about the possibility that we may eventually be able to grow replacement cells in the laboratory, getting around some of the problems of transplant immunology and perhaps even replacing cells that are not ordinarily thought to have much reparative capacity. There has also been concern, especially over the use of fetal tissue to obtain stem cells. While it is a familiar idea that the bone marrow may contain stem cells capable of differentiating along several pathways, it’s only recently that differentiation to non-hematopoietic, non-stromal cells has been claimed. The water is muddied a bit by the fact that cells may acquire characteristics of another cell line by fusion rather than de- or re-differentiation, so it can be difficult to parse out just what has happened in a specific experiment. A chapter in this story is presented on page 230 this month by Dr Baijun Fang, et alii from the Chinese Academy of Medical Sciences and Peking Union Medical College. These researchers isolated mononuclear cells from human fetal bone marrow, and depleted them of CD-45-positive, glycophorin-A-positive and CD-34-positive cells. They then cultured the cells by limiting dilution