Unexpected outcome (positive or negative) including adverse drug reactions

Extravascular lipid deposit (xanthelasma) induced by a plant sterol-enriched margarine

Bruno Vergès, Anne Athias, Jean-Michel Petit, Marie-Claude Brindisi

Hôpital du Bocage, 2 Bd Maréchal de Lattre de Tassigny, Dijon 21000, France

Correspondence to:
Bruno Vergès, bruno.verges{at}chu-dijon.fr

Plant sterol-enriched margarine consumption is known to significantly reduce concentrations of plasma low density lipoprotein (LDL) cholesterol. However, there is no evidence that such margarines may reduce cardiovascular events. This is the first report of a significant increase in the plasma concentration of phytosterols due to plant sterol-enriched margarine consumption leading to extravascular lipid deposits (xanthelasma), in a woman with hypercholesterolaemia. Because increased plasma levels of phytosterols may promote atherosclerosis, the present observation raises concern about potential cardiovascular risk after long-term consumption of these margarines.

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Plant sterol-enriched margarines have been available for several years and have been shown to lower concentrations of plasma low density lipoprotein (LDL) cholesterol by reducing intestinal cholesterol absorption.^1,2 At the usual recommended intakes of 2 to 2.5 g/day, margarines enriched with plant sterols lower plasma LDL cholesterol concentrations by 10% to 14%.² Despite this significant reduction, such margarines have not been shown prospectively to reduce cardiovascular events. We report for the first time the case of extravascular lipid deposits (xanthelasma) associated with increased plasma phytosterol levels induced by a regimen of margarine enriched with plant sterols in a woman with hypercholesterolaemia.

A 59-year-old woman without a history of coronary disease was referred to our department because of hypercholesterolaemia. The woman had previously experienced myalgia when taking statins (pravastatin, fluvastatin) or fibrates (fenofibrate) and gastrointestinal disorders when taking colestyramine. Because of these side effects, all hypolipidaemic drug therapies had been discontinued. Three months after the woman started a controlled diet, her LDL cholesterol concentration remained elevated (5.75 mmol/l). Because she was intolerant to hypolipidaemic agents, we recommended that she consume a plant sterol-enriched margarine at the recommended dose of 20 g/day (Fruit d’Or Pro-activ margarine, containing 8% phytosterols), corresponding to 1.6 g/day phytosterols. After 18 months of regular consumption of plant sterol-enriched margarine, the patient developed xanthelasma (fig 1), whereas her plasma LDL cholesterol level was 4.49 mmol/l. This rapid development of xanthelasma associated with an only moderately elevated concentration of plasma LDL cholesterol prompted us to measure this patient’s plasma phytosterol concentration (campesterol), which was significantly increased (165 µmol/l; normal <25 µmol/l).

View this figure (116K): in this window | in a new window | PowerPoint for Teaching   Figure 1 Extravascular lipid deposits (xanthelasma) (arrows) in the patient treated with margarine enriched in plant sterols.

 

We asked the patient to discontinue her consumption of plant sterol-enriched margarine. Three months later, her plasma campesterol levels were normal (20 µmol/l; normal <25 µmol/l) (fig 2). No mutations of ABCG5/ABCG8 transporters were found in this patient, ruling out a "minor form" of phytosterolaemia (or sitosterolaemia).³

View this figure (13K): in this window | in a new window | PowerPoint for Teaching   Figure 2 Evolution of plasma LDL cholesterol () and campesterol (•) in a patient while using plant sterol-enriched margarine and after its use had been discontinued. ULN: upper limit of the normal range.

 

We report, for the first time, a significant increase in plasma concentrations of phytosterols due to plant sterol-enriched margarine leading to extravascular lipid deposits (xanthelasma). Although our patient had no sitosterolaemia (she had no ABCG5/ABCG8 mutation, and her plasma campesterol concentrations returned to normal after withdrawal of plant sterol-enriched margarine), she had elevated plasma concentrations of phytosterols. In our patient, the plasma concentration of campesterol was not as high as is usually observed in familial sitosterolaemia but was more than 6 times the upper limit of normal values, which is not negligible. The rise in plasma campesterol observed in our patient was greater than the mean 90% increase usually reported in clinical trials of plant sterol-enriched margarine.^4,5 The reasons for this discrepancy are not clear, but several studies in humans have shown a heterogeneous level of increase in plasma campesterol after consumption of plant sterol-enriched margarine.^4–6 Several different mechanisms are responsible for plasma campesterol concentrations, which are influenced by other genes beside ABCG5/ABCG8.⁶ The heterogeneous levels of increase in plasma campesterol after consumption of plant sterol-enriched margarine could be due to genetic diversity in the general population. Thus, some individuals may show a larger increase in plasma campesterol after consumption of plant sterol-enriched margarine than others.

Patients with sitosterolaemia show extravascular lipid deposits and premature severe atherosclerosis.⁷ Promotion of atherosclerosis in patients with sitosterolaemia has been shown to be related to augmented plasma phytosterol concentrations.⁸ Thus, the increase in plasma phytosterol concentrations due to plant sterol-enriched margarines could be harmful, and we cannot exclude that long-term consumption of plant sterol-enriched margarines may increase cardiovascular risk. Indeed, although plant sterol-enriched margarines diminish the plasma LDL cholesterol concentration, they have not been shown to reduce cardiovascular risk.⁸ Our present observation showing a large increase in plasma phytosterols and extravascular lipid deposits (xanthelasma) due to a regimen of plant sterol-enriched margarine raises concern about potential cardiovascular risk after long-term consumption of these margarines.

Competing interests: none.

Patient consent: Patient/guardian consent was obtained for publication.

1. Normén, L, Dutta, P, Lia, A, et al. Soy sterol esters and β-sitostanol ester as inhibitors of cholesterol absorption in human small bowel. Am J Clin Nutr 2000; 71: 908–13.[Abstract/Free Full Text]
2. Plat, J, & Mensink, RP. Plant stanol and sterol esters in the control of blood cholesterol levels: mechanism and safety aspects. Am J Cardiol 2005; 96(1 Suppl): 15–22.
3. Lu, K, Lee, MH, Hazard, S, et al. Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively. Am J Hum Genet 2001; 69: 278–90.[CrossRef][Medline]
4. Mussner, MJ, Parhofer, KG, Von Bergmann, K, et al. Effects of phytosterol ester-enriched margarine on plasma lipoproteins in mild to moderate hypercholesterolemia are related to basal cholesterol and fat intake. Metabolism 2002; 51: 189–94.[CrossRef][Medline]
5. Fransen, HP, de Jong, N, Wolfs, M, et al. Customary use of plant sterol and plant stanol enriched margarine is associated with changes in serum plant sterol and stanol concentrations in humans. J Nutr 2007; 137: 1301–6.[Abstract/Free Full Text]
6. von Bergmann, K, Sudhop, T, & Lütjohann, D. Cholesterol and plant sterol absorption: recent insights. Am J Cardiol 2005; 96(1 Suppl): 10–14.[CrossRef]
7. Salen, G, Horak, I, Rothkopf, M, et al. Lethal atherosclerosis associated with abnormal plasma and tissue sterol composition in sitosterolemia with xanthomatosis. J Lipid Res 1985; 26: 1126–33.[Abstract]
8. Katan, MB, Grundy, SM, Jones, P, et al. Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels. Mayo Clin Proc 2003; 78: 965–78.[Abstract/Free Full Text]

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