Sitosterolaemia: Pathophysiology, clinical presentation and laboratory diagnosis

Division of Endocrinology (Department of Medicine), Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Journal of clinical pathology (Impact Factor: 2.92). 06/2008; 61(5):588-94. DOI: 10.1136/jcp.2007.049775
Source: PubMed


Sitosterolaemia is an extremely rare autosomal recessive disease, the key feature of which is the impairment of pathways that normally prevent absorption and retention of non-cholesterol sterols, for example plant sterols and shellfish sterols. The clinical manifestations are akin to familial hypercholesterolaemia (such as presence of tendon xanthomas and premature atherosclerosis), but with "normal to moderately elevated" cholesterol levels. The gene(s) causing sitosterolaemia was mapped to the STSL locus on human chromosome 2p21, and mutations in either of the two genes that comprise this locus, ABCG5 or ABCG8, cause this disease. Exact prevalence is unknown, but there are estimated to be 80-100 cases around the world. This rare disease has shed light into the molecular mechanisms that control sterol trafficking in the enterocyte and hepatocyte; ABCG5 and ABCG8 heterodimerise to form a sterol efflux transporter in the liver and intestine. In this review the pathophysiology, clinical manifestations and approach to clinical and laboratory diagnosis of this disease are described.

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Available from: Shailendra B Patel, Oct 03, 2015
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    • "Two major features differentiate sitosterolaemia from HoFH: (i) markedly (>30-fold) increased plasma concentrations of plant sterols,18 and (ii) elevated cholesterol levels, which respond well to diet and bile acid sequestrants or ezetimibe and may not persist after the first two decades of life.18,19 Diagnosis is confirmed by genetic analysis, with mutations in two ATP binding cassette transporter genes, ABCG5 and/or ABCG8, shown to be causative for sitosterolaemia.18 "
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    ABSTRACT: Aims: Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH. Methods and results: Early diagnosis of HoFH and prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH. We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensive ACVD evaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years, or less if deemed necessary. Conclusion: This EAS Consensus Panel highlights the need for early identification of HoFH patients, prompt referral to specialized centres, and early initiation of appropriate treatment. These recommendations offer guidance for a wide spectrum of clinicians who are often the first to identify patients with suspected HoFH.
    European Heart Journal 07/2014; 35(32). DOI:10.1093/eurheartj/ehu274 · 15.20 Impact Factor
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    • "The discovery of phytosterolemia, a rare inherited disorder, has raised curiosity as to whether phytosterols could be a possible risk factor for cardiovascular disease [17] [18]. Elevated phytosterol concentrations , xanthomas and the premature onset of atherosclerosis are the significant findings in patients with homozygous phytosterolemia . "
    Biochemical and Biophysical Research Communications 01/2014; DOI:10.1016/j.bbrc.2014.01.147. · 2.30 Impact Factor
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    • "The presentation of these clinical signs varies based on the level of PS retention in tissues. The exact prevalence of STSL is unknown with only 100 known cases identified worldwide [10]. The diagnosis of this disease relies on confirming elevated plasma levels of sitosterol, which are normally below 0.4 mg/dl [11], through the use of high-performance liquid chromatography or gas chromatography. "
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    ABSTRACT: Sitosterolemia (STSL) is a rare autosomal recessive disease, manifested by extremely elevated plant sterols (PS) in plasma and tissue, leading to xanthoma and premature atherosclerotic disease. Therapeutic approaches include limiting PS intake, interrupting enterohepatic circulation of bile acid using bile acid binding resins such as cholestyramine, and/or ileal bypass, and inhibiting intestinal sterol absorption by ezetimibe (EZE). The objective of this review is to evaluate sterol metabolism in STSL and the impact of the currently available treatments on sterol trafficking in this disease. The role of PS in initiation of xanthomas and premature atherosclerosis is also discussed. Blocking sterols absorption with EZE has revolutionized STSL patient treatment as it reduces circulating levels of non-cholesterol sterols in STSL. However, none of the available treatments including EZE have normalized plasma PS concentrations. Future studies are needed to: (i) explore where cholesterol and non-cholesterol sterols accumulate, (ii) assess to what extent these sterols in tissues can be mobilized after blocking their absorption, and (iii) define the factors governing sterol flux.
    Atherosclerosis 12/2013; 231(2):291–299. DOI:10.1016/j.atherosclerosis.2013.09.038 · 3.99 Impact Factor
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