The natural history of phytosterolemia: Observations on its homeostasis


      Background and aims

      Phytosterolemia is a rare genetic disease caused by mutation of the ABCG5/8 gene. Our aim was to elucidate the natural history and homeostasis of phytosterolemia.


      We analyzed a Hutterite kindred consisting of 21 homozygotes with phytosterolemia assembled over a period of two decades, all of whom carried the ABCG8 S107X mutation and were treated with ezetimibe.


      Most of these subjects were asymptomatic and devoid of clinical stigmata, and this, since they were ascertained primarily by a process of cascade testing, suggests that, relative to its true prevalence, phytosterolemia is a condition of low morbidity. All subjects have responded well to treatment with ezetimibe. Initial (pre-treatment) and post-ezetimibe levels of cholesterol and sitosterol were measured and percentage changes on ezetimibe were calculated. We found initial levels to be inversely related to subjects' ages as were percentage responses to ezetimibe therapy. There was also a direct correlation between initial levels and percentage responses to ezetimibe. Hence on-treatment levels were very uniform.


      This evidence of a link with age leads us to propose that an age-related change in cholesterol and sterol homeostasis occurs at puberty in phytosterolemia and that the change is due to high sterol and/or stanol levels causing feedback inhibition of sterol regulatory element-binding protein (SREBP-2) processing. This would explain the well-documented phenomenon of depressed cholesterol synthesis in phytosterolemia. It is also well-known that LDL-receptor activity is increased, and this feasibly explains reduced LDL levels and consequent reduction of plasma cholesterol and sitosterol levels. Downregulated SREBP-2 processing would be expected to also lower proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and this would explain high LDL-receptor activity. The above state could be termed disrupted homeostasis and the alternative, seen mostly in children and characterized by hypercholesterolemia and hypersterolemia, simple homeostasis.



      ABCG8 (ATP-binding cassette sub-family G member 8), SREBP-2 (Sterol regulatory element-binding protein 2), LDL (low-density lipoprotein), HMGCR (3-Hydroxy-3-Methylglutaryl-CoA reductase), PCSK9 (Proprotein convertase subtilisin/kexin type 9), LDLR (Low-density lipoprotein receptor.)
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        • Bhattacharyya A.K.
        • Connor W.E.
        Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters.
        J. Clin. Invest. 1974 Apr; 53: 1033-1043
        • Kidambi S.
        • Patel S.B.
        Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis.
        J. Clin. Pathol. 2008 May; 61: 588-594
        • Patel S.B.
        Plant sterols and stanols: their role in Health and disease.
        J. Clin. Lipidol. 2008 Apr; 2: S11-S19
        • Mymin D.
        • Wang J.
        • Frohlich J.
        • Hegele R.A.
        Image in cardiovascular medicine. Aortic xanthomatosis with coronary ostial occlusion in a child homozygous for a nonsense mutation in ABCG8.
        Circulation. 2003; 107: 791
        • Chong J.X.
        • Ouwenga R.
        • Anderson R.L.
        • Waggoner D.J.
        • Ober C.
        A population-based study of autosomal-recessive disease-causing mutations in a founder population.
        Am. J. Hum. Genet. 2012 Oct 5; 91: 608-620
        • Lütjohann D.
        • von Bergmann K.
        • Sirah W.
        • Macdonell G.
        • Johnson-Levonas A.O.
        • Shah A.
        • Lin J.
        • Sapre A.
        • Musliner T.
        Long-term efficacy and safety of ezetimibe 10 mg in patients with homozygous sitosterolemia: a 2-year, open-label extension study.
        Int. J. Clin. Pract. 2008 Oct; 62: 1499-1510
        • Othman R.A.
        • Myrie S.B.
        • Mymin D.
        • Merkens L.S.
        • Roullet J.B.
        • Steiner R.D.
        • Jones P.J.
        Ezetimibe reduces plant sterol accumulation and favorably increases platelet count in sitosterolemia.
        J. Pediatr. 2015 Jan; 166: 125-131
        • Lee M.H.
        • Lu K.
        • Patel S.B.
        Genetic basis of sitosterolemia.
        Curr. Opin. Lipidol. 2001 Apr; 12: 141-149
        • Boberg K.M.
        • Akerlund J.E.
        • Björkhem I.
        Effect of sitosterol on the rate-limiting enzymes in cholesterol synthesis and degradation.
        Lipids. 1989 Jan; 24: 9-12
        • Nguyen L.B.
        • Shefer S.
        • Salen G.
        • Ness G.C.
        • Tint G.S.
        • Zaki F.G.
        • Rani I.
        A molecular defect in hepatic cholesterol biosynthesis in sitosterolemia with xanthomatosis.
        J. Clin. Invest. 1990 Sep; 86: 923-931
        • Nguyen L.B.
        • Salen G.
        • Shefer S.
        • Tint G.S.
        • Shore V.
        • Ness G.C.
        Decreased cholesterol biosynthesis in sitosterolemia with xanthomatosis: diminished mononuclear leukocyte 3- hydroxy-3-methylglutaryl coenzyme A reductase activity and enzyme protein associated with increased low-density lipoprotein receptor function.
        Metabolism. 1990 Apr; 39: 436-443
        • Honda A.
        • Salen G.
        • Nguyen L.B.
        • Tint G.S.
        • Batta A.K.
        • Shefer S.
        Down-regulation of cholesterol biosynthesis in sitosterolemia: diminished activities of acetoacetyl-CoA thiolase, 3-hydroxy-3-methylglutaryl-CoA synthase, reductase, squalene synthase, and 7-dehydrocholesterol delta7-reductase in liver and mononuclear leukocytes.
        J. Lipid Res. 1998 Jan; 39: 44-50
        • Brown M.S.
        • Goldstein J.L.
        The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor.
        Cell. May 2, 1997; 89: 331-340
        • Salen G.
        • Kwiterovich P.O.
        • Shefer S.
        • Tint G.S.
        • Horak I.
        • Shore V.
        • Dayal B.
        • Horak E.
        Increased plasma cholestanol and 5a-saturated plant sterol derivatives in subjects with sitosterolemia and xanthomatosis.
        J. Lipid Res. 1985; 26: 203-209
        • Shefer S.
        • Salen G.
        • Nguyen L.
        • Batta A.K.
        • Packin V.
        • Tint G.S.
        Hauser S.J. Competitive inhibition of bile acid synthesis by endogenous cholestanol and sitosterol in sitosterolemia with xanthomatosis. Effect on cholesterol 7 alpha-hydroxylase.
        Clin. Invest. 1988 Dec; 82: 1833-1839
        • Shefer S.
        • Salen G.
        • Bullock J.
        • Nguyen L.B.
        • Ness G.C.
        • Vhao Z.
        • Belamarich P.F.
        • Chowdhary I.
        • Lerner S.
        • K.Batta A.
        • Tint G.S.
        The effect of increased hepatic sitosterol on the regulation of 3-hydroxy-3-meth-yl glutaryl-coenzyme A reductase and cholesterol 7a-hydroxylase in the rat and sitosterolemic homozygotes.
        Hepatology. 1994; 20: 213-219
        • Yang C.
        • Yu L.
        • Li W.
        • Xu F.
        • Cohen J.C.
        • Hobbs H.H.
        Disruption of cholesterol homeostasis by plant sterols.
        J. Clin. Invest. 2004; 114: 813-822
        • Goldstein J.L.
        • Brown M.S.
        A century of cholesterol and coronaries: from plaques to genes to statins.
        Cell. 2015; 161: 161-172
        • Hansel B.
        • Carrié A.
        • Brun-Druc N.
        • Leclert G.
        • Chantepie S.
        • Coiffard A.S.
        • Kahn J.F.
        • Chapman M.J.
        • Bruckert E.
        Premature atherosclerosis is not systematic in phytosterolemic patients: severe hypercholesterolemia as a confounding fa ctor in five subjects.
        Atherosclerosis. 2014; 234: 162-168
        • Nguyen L.B.
        • Salen G.
        • Shefer S.
        • Tint G.S.
        • Ruiz F.
        Macrophage 3-hydroxy-3- methylglutaryl coenzyme a reductase activity in sitosterolemia: effects of increased cellular cholesterol and sitosterol concentrations.
        Metabolism. 2001 Oct; 50: 1224-1229