Skip to main content

Advertisement

SpringerLink
Log in

Sitosterolemia: Diagnosis, Investigation, and Management

  • Rare Diseases and Lipid Metabolism (JAG López, Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Sitosterolemia is a rare autosomal recessively inherited disease caused by mutations affecting ABCG5 or ABCG8, which are located on human chromosome band 2p21. Around 100 cases have been reported in the literature. Sitosterolemic patients typically exhibit a 30-fold to 100-fold increase in plasma concentrations of plant sterols. The clinical manifestations include xanthomas, premature atherosclerosis, hemolytic anemia, and macrothrombocytopenia. It is noteworthy that abnormal hematological parameters may be the only clinical feature of sitosterolemic patients, suggesting that sitosterolemia may be more frequent than previously thought. Severe accumulation of plant sterols in mouse models of sitosterolemia induced complex cardiac lesions, anemia, and macrothrombocytopenia, disrupted adrenal and liver cholesterol homeostasis, and caused infertility and hypertriglyceridemia. It remains unclear whether all disease traits are present in sitosterolemic patients. The drug ezetimibe appears to be effective in reducing plasma plant sterol levels, promotes xanthoma regression, and improves the cardiovascular and hematological signs in sitosterolemic patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Patel SB, Salen G, Hidaka H, Kwiterovich PO, Stalenhoef AF, Miettinen TA, et al. Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21. J Clin Invest. 1998;102(5):1041–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 2000;290(5497):1771–5.

    Article  CAS  PubMed  Google Scholar 

  3. Lee MH, Lu K, Hazard S, Yu H, Shulenin S, Hidaka H, et al. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet. 2001;27(1):79–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Kidambi S, Patel SB. Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis. J Clin Pathol. 2008;61(5):588–94.

    Article  CAS  PubMed  Google Scholar 

  5. Merkens LS, Myrie SB, Steiner RD, Mymin D. Sitosterolemia. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJH, Stephens K, editors. GeneReviews. Seattle: University of Washington; 1993–2014. http://www.ncbi.nlm.nih.gov/books/NBK131810/.

  6. Salen G, Shefer S, Nguyen L, Ness GC, Tint GS, Shore V. Sitosterolemia. J Lipid Res. 1992;33(7):945–55.

    CAS  PubMed  Google Scholar 

  7. Othman RA, Myrie SB, Jones PJ. Non-cholesterol sterols and cholesterol metabolism in sitosterolemia. Atherosclerosis. 2013;231(2):291–9. This timely review discusses recent findings on sterol metabolism alterations in sitosterolemic patients.

    Article  CAS  PubMed  Google Scholar 

  8. Hazard SE, Patel SB. Sterolins ABCG5 and ABCG8: regulators of whole body dietary sterols. Pflugers Arch. 2007;453(5):745–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Lu K, Lee MH, Yu H, Zhou Y, Sandell SA, Salen G, et al. Molecular cloning, genomic organization, genetic variations, and characterization of murine sterolin genes Abcg5 and Abcg8. J Lipid Res. 2002;43(4):565–78.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Yu H, Pandit B, Klett E, Lee MH, Lu K, Helou K, et al. The rat STSL locus: characterization, chromosomal assignment, and genetic variations in sitosterolemic hypertensive rats. BMC Cardiovasc Disord. 2003;3:4.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Lee MH, Gordon D, Ott J, Lu K, Ose L, Miettinen T, et al. Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolaemia in multiple communities. Eur J Hum Genet. 2001;9(5):375–84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Heum Park J, Chung IH, Hyun Kim D, Ho Choi M, Garg A, Yoo EG. Sitosterolemia presenting with severe hypercholesterolemia and intertriginous xanthomas in a breastfed infant: case report and brief review. J Clin Endocrinol Metab. 2014. doi:10.1210/jc.2013-3274.

    Google Scholar 

  13. Wang J, Joy T, Mymin D, Frohlich J, Hegele RA. Phenotypic heterogeneity of sitosterolemia. J Lipid Res. 2004;45(12):2361–7.

    Article  CAS  PubMed  Google Scholar 

  14. Wang Z, Cao L, Su Y, Wang G, Wang R, Yu Z, et al. Specific macrothrombocytopenia/hemolytic anemia associated with sitosterolemia. Am J Hematol. 2014;89(3):320–4.

    Article  CAS  PubMed  Google Scholar 

  15. Calpe-Berdiel L, Escola-Gil JC, Blanco-Vaca F. New insights into the molecular actions of plant sterols and stanols in cholesterol metabolism. Atherosclerosis. 2009;203(1):18–31.

    Article  CAS  PubMed  Google Scholar 

  16. Davis Jr HR, Zhu LJ, Hoos LM, Tetzloff G, Maguire M, Liu J, et al. Niemann-Pick C1 like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis. J Biol Chem. 2004;279(32):33586–92.

    Article  CAS  PubMed  Google Scholar 

  17. Tang W, Ma Y, Jia L, Ioannou YA, Davies JP, Yu L. Genetic inactivation of NPC1L1 protects against sitosterolemia in mice lacking ABCG5/ABCG8. J Lipid Res. 2009;50(2):293–300.

    Article  CAS  PubMed  Google Scholar 

  18. Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, et al. The target of ezetimibe is Niemann-Pick C1-like 1 (NPC1L1). Proc Natl Acad Sci U S A. 2005;102(23):8132–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Yamanashi Y, Takada T, Suzuki H. Niemann-Pick C1-like 1 overexpression facilitates ezetimibe-sensitive cholesterol and β-sitosterol uptake in CaCo-2 cells. J Pharmacol Exp Ther. 2007;320(2):559–64.

    Article  CAS  PubMed  Google Scholar 

  20. Kwon HJ, Palnitkar M, Deisenhofer J. The structure of the NPC1L1 N-terminal domain in a closed conformation. PLoS One. 2011;6(4):e18722.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Temel RE, Gebre AK, Parks JS, Rudel LL. Compared with acyl-CoA:cholesterol O-acyltransferase (ACAT) 1 and lecithin:cholesterol acyltransferase, ACAT2 displays the greatest capacity to differentiate cholesterol from sitosterol. J Biol Chem. 2003;278(48):47594–601.

    Article  CAS  PubMed  Google Scholar 

  22. Nguyen TM, Sawyer JK, Kelley KL, Davis MA, Kent CR, Rudel LL. ACAT2 and ABCG5/G8 are both required for efficient cholesterol absorption in mice: evidence from thoracic lymph duct cannulation. J Lipid Res. 2012;53(8):1598–609.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Myrie SB, Mymin D, Triggs-Raine B, Jones PJ. Serum lipids, plant sterols, and cholesterol kinetic responses to plant sterol supplementation in phytosterolemia heterozygotes and control individuals. Am J Clin Nutr. 2012;95(4):837–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Brauner R, Johannes C, Ploessl F, Bracher F, Lorenz RL. Phytosterols reduce cholesterol absorption by inhibition of 27-hydroxycholesterol generation, liver X receptor α activation, and expression of the basolateral sterol exporter ATP-binding cassette A1 in Caco-2 enterocytes. J Nutr. 2013;142(6):981–9. This article shows that plant sterols interfere with the formation of 27-hydroxycholesterol in intestinal cells and repress ABCA1-mediated incorporation of cholesterol into HDL.

    Article  Google Scholar 

  25. Abumrad NA, Davidson NO. Role of the gut in lipid homeostasis. Physiol Rev. 2012;92(3):1061–85.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Miettinen TA, Klett EL, Gylling H, Isoniemi H, Patel SB. Liver transplantation in a patient with sitosterolemia and cirrhosis. Gastroenterology. 2006;130(2):542–7.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Park Y, Carr TP. Unsaturated fatty acids and phytosterols regulate cholesterol transporter genes in Caco-2 and HepG2 cell lines. Nutr Res. 2013;33(2):154–61.

    Article  CAS  PubMed  Google Scholar 

  28. Rosenblat M, Volkova N, Aviram M. Pomegranate phytosterol (β-sitosterol) and polyphenolic antioxidant (punicalagin) addition to statin, significantly protected against macrophage foam cells formation. Atherosclerosis. 2013;226(1):110–7.

    Article  CAS  PubMed  Google Scholar 

  29. Kruit JK, Drayer AL, Bloks VW, Blom N, Olthof SG, Sauer PJ, et al. Plant sterols cause macrothrombocytopenia in a mouse model of sitosterolemia. J Biol Chem. 2008;283(10):6281–7.

    Article  CAS  PubMed  Google Scholar 

  30. Yang C, Yu L, Li W, Xu F, Cohen JC, Hobbs HH. Disruption of cholesterol homeostasis by plant sterols. J Clin Invest. 2004;114(6):813–22.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Solca C, Tint GS, Patel SB. Dietary xenosterols lead to infertility and loss of abdominal adipose tissue in sterolin-deficient mice. J Lipid Res. 2013;54(2):397–409. This study explores the mechanisms by which two mouse models of sitosterolemia show infertility and loss of abdominal fat.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Mushtaq T, Wales JK, Wright NP. Adrenal insufficiency in phytosterolaemia. Eur J Endocrinol. 2007;157 Suppl 1:S61–5.

    Article  CAS  PubMed  Google Scholar 

  33. Mymin D, Wang J, Frohlich J, Hegele RA. Image in cardiovascular medicine. Aortic xanthomatosis with coronary ostial occlusion in a child homozygous for a nonsense mutation in ABCG8. Circulation. 2003;107(5):791.

    Article  PubMed  Google Scholar 

  34. Cheng WF, Yuen YP, Chow CB, Au KM, Chan YW, Tam SC. Sitosterolaemia and xanthomatosis in a child. Hong Kong Med J. 2003;9(3):206–9.

    CAS  PubMed  Google Scholar 

  35. Salen G, Horak I, Rothkopf M, Cohen JL, Speck J, Tint GS, et al. Lethal atherosclerosis associated with abnormal plasma and tissue sterol composition in sitosterolemia with xanthomatosis. J Lipid Res. 1985;26(9):1126–33.

    CAS  PubMed  Google Scholar 

  36. Bao L, Li Y, Deng SX, Landry D, Tabas I. Sitosterol-containing lipoproteins trigger free sterol-induced caspase-independent death in ACAT-competent macrophages. J Biol Chem. 2006;281(44):33635–49.

    Article  CAS  PubMed  Google Scholar 

  37. Sabeva NS, McPhaul CM, Li X, Cory TJ, Feola DJ, Graf GA. Phytosterols differentially influence ABC transporter expression, cholesterol efflux and inflammatory cytokine secretion in macrophage foam cells. J Nutr Biochem. 2011;22(8):777–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Rubis B, Paszel A, Kaczmarek M, Rudzinska M, Jelen H, Rybczynska M. Beneficial or harmful influence of phytosterols on human cells? Br J Nutr. 2008;100(6):1183–91.

    Article  CAS  PubMed  Google Scholar 

  39. O'Callaghan Y, McCarthy FO, O'Brien NM. Recent advances in phytosterol oxidation products. Biochem Biophys Res Commun. 2014. doi:10.1016/j.bbrc.2014.01.148.

    PubMed  Google Scholar 

  40. McDaniel AL, Alger HM, Sawyer JK, Kelley KL, Kock ND, Brown JM, et al. Phytosterol feeding causes toxicity in ABCG5/G8 knockout mice. Am J Pathol. 2013;182(4):1131–8. This study shows that a high-plant-sterol diet is extremely toxic to sitosterolemic mice and induces liver abnormalities and severe cardiac lesions.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Mendez-Gonzalez J, Julve J, Rotllan N, Llaverias G, Blanco-Vaca F, Escola-Gil JC. ATP-binding cassette G5/G8 deficiency causes hypertriglyceridemia by affecting multiple metabolic pathways. Biochim Biophys Acta. 2011;1811(12):1186–93.

    Article  CAS  PubMed  Google Scholar 

  42. Su K, Sabeva NS, Liu J, Wang Y, Bhatnagar S, van der Westhuyzen DR, et al. The ABCG5 ABCG8 sterol transporter opposes the development of fatty liver disease and loss of glycemic control independently of phytosterol accumulation. J Biol Chem. 2011;287(34):28564–75.

    Article  Google Scholar 

  43. Mannucci L, Guardamagna O, Bertucci P, Pisciotta L, Liberatoscioli L, Bertolini S, et al. Beta-sitosterolaemia: a new nonsense mutation in the ABCG5 gene. Eur J Clin Invest. 2007;37(12):997–1000.

    Article  CAS  PubMed  Google Scholar 

  44. Salen G, von Bergmann K, Lutjohann D, Kwiterovich P, Kane J, Patel SB, et al. Ezetimibe effectively reduces plasma plant sterols in patients with sitosterolemia. Circulation. 2004;109(8):966–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Hidaka H, Nakamura T, Aoki T, Kojima H, Nakajima Y, Kosugi K, et al. Increased plasma plant sterol levels in heterozygotes with sitosterolemia and xanthomatosis. J Lipid Res. 1990;31(5):881–8.

    CAS  PubMed  Google Scholar 

  46. Su Y, Wang Z, Yang H, Cao L, Liu F, Bai X, et al. Clinical and molecular genetic analysis of a family with sitosterolemia and co-existing erythrocyte and platelet abnormalities. Haematologica. 2006;91(10):1392–5.

    CAS  PubMed  Google Scholar 

  47. Rees DC, Iolascon A, Carella M, O'Marcaigh AS, Kendra JR, Jowitt SN, et al. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol. 2005;130(2):297–309.

    Article  CAS  PubMed  Google Scholar 

  48. Chase TH, Lyons BL, Bronson RT, Foreman O, Donahue LR, Burzenski LM, et al. The mouse mutation “thrombocytopenia and cardiomyopathy” (trac) disrupts Abcg5: a spontaneous single gene model for human hereditary phytosterolemia/sitosterolemia. Blood. 2010;115(6):1267–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Kanaji T, Kanaji S, Montgomery RR, Patel SB, Newman PJ. Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia. Blood. 2013;122(15):2732–42. This study describes the mechanistic impact of plant sterols on the platelet phenotype and functionality in a mouse model of sitosterolemia.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Matsuo M. ATP-binding cassette proteins involved in glucose and lipid homeostasis. Biosci Biotechnol Biochem. 2010;74(5):899–907.

    Article  CAS  PubMed  Google Scholar 

  51. Wang G, Cao L, Wang Z, Jiang M, Sun X, Bai X, et al. Macrothrombocytopenia/stomatocytosis specially associated with phytosterolemia. Clin Appl Thromb Hemost. 2012;18(6):582–7. This study highlights a clinically relevant concern for physicians in recognizing blood cell dysmorphologies associated with sitosterolemia, with most sitosterolemic patients studied initially misdiagnosed with other chronic thrombocytopenias and, consequently, treated incorrectly.

    Article  CAS  PubMed  Google Scholar 

  52. Neff AT. Sitosterolemia's stomatocytosis and macrothrombocytopenia. Blood. 2012;120(22):4283.

    Article  PubMed  Google Scholar 

  53. Quintás-Cardama A, McCarthy JJ. Long-term follow-up of a patient with sitosterolemia and hemolytic anemia with excellent response to ezetimibe. J Genet Disord Genet Rep. 2013;2:1. This short report describes the long-term follow-up of a patient with sitosterolemia associated with hemolytic anemia, successfully managed with ezetimibe.

    Google Scholar 

  54. Tsubakio-Yamamoto K, Nishida M, Nakagawa-Toyama Y, Masuda D, Ohama T, Yamashita S. Current therapy for patients with sitosterolemia – effect of ezetimibe on plant sterol metabolism. J Atheroscler Thromb. 2010;17(9):891–900.

    Article  CAS  PubMed  Google Scholar 

  55. Connor WE, Lin DS, Pappu AS, Frohlich J, Gerhard G. Dietary sitostanol and campestanol: accumulation in the blood of humans with sitosterolemia and xanthomatosis and in rat tissues. Lipids. 2005;40(9):919–23.

    Article  CAS  PubMed  Google Scholar 

  56. Solca C, Stanga Z, Pandit B, Diem P, Greeve J, Patel SB. Sitosterolaemia in Switzerland: molecular genetics links the US Amish-Mennonites to their European roots. Clin Genet. 2005;68(2):174–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Salen G, Starc T, Sisk CM, Patel SB. Intestinal cholesterol absorption inhibitor ezetimibe added to cholestyramine for sitosterolemia and xanthomatosis. Gastroenterology. 2006;130(6):1853–7.

    Article  PubMed  Google Scholar 

  58. Hung C-N, Lee C-Y. A case of sitosterolaemia with stomatocyticanaemia and thrombocytopenia treated with ezetimibe with good response. Int J Pediatr Endocrinol. 2013;2013 Suppl 1:174.

    Article  Google Scholar 

  59. Drozdowski LA, Clandinin T, Thomson AB. Ontogeny, growth and development of the small intestine: understanding pediatric gastroenterology. World J Gastroenterol. 2010;16(7):787–99.

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Niu DM, Chong KW, Hsu JH, Wu TJ, Yu HC, Huang CH, et al. Clinical observations, molecular genetic analysis, and treatment of sitosterolemia in infants and children. J Inherit Metab Dis. 2010;33(4):437–43.

    Article  CAS  PubMed  Google Scholar 

  61. Davis HR, Veltri EP. Zetia: inhibition of Niemann-Pick C1 like 1 (NPC1L1) to reduce intestinal cholesterol absorption and treat hyperlipidemia. J Atheroscler Thromb. 2007;14(3):99–108.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was partly funded by the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, CP13-00070 (to Josep Julve), CD12-00533 (to Helena Quesada), FIS 11-0176 (to Francisco Blanco-Vaca), and FIS 12-00291 (to Joan Carles Escolà-Gil).

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Joan Carles Escolà-Gil, Helena Quesada, Josep Julve, Jesús M. Martín-Campos, Lídia Cedó, and Francisco Blanco-Vaca declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Institut d’Investigacions Biomèdiques (IIB) Sant Pau, Sant Antoni Maria Claret 167, 08025, Barcelona, Spain

    Joan Carles Escolà-Gil, Helena Quesada, Josep Julve, Jesús M. Martín-Campos, Lídia Cedó & Francisco Blanco-Vaca

  2. CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, C/ Monforte de Lemos 3-5, 28029, Madrid, Spain

    Joan Carles Escolà-Gil, Helena Quesada, Josep Julve, Jesús M. Martín-Campos, Lídia Cedó & Francisco Blanco-Vaca

  3. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Campus de Bellaterra, 08193, Barcelona, Spain

    Joan Carles Escolà-Gil, Josep Julve, Jesús M. Martín-Campos & Francisco Blanco-Vaca

  4. Servei de Bioquímica, Hospital de la Santa Creu i Sant Pau, C/ Sant Quintí 89, 08041, Barcelona, Spain

    Francisco Blanco-Vaca

Authors
  1. Joan Carles Escolà-Gil
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helena Quesada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Josep Julve
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jesús M. Martín-Campos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lídia Cedó
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Francisco Blanco-Vaca
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francisco Blanco-Vaca.

Additional information

Joan Carles Escolà-Gil and Helena Quesada contributed equally to this work.

This article is part of the Topical Collection on Rare Diseases and Lipid Metabolism

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Escolà-Gil, J.C., Quesada, H., Julve, J. et al. Sitosterolemia: Diagnosis, Investigation, and Management. Curr Atheroscler Rep 16, 424 (2014). https://doi.org/10.1007/s11883-014-0424-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11883-014-0424-2

Keywords

Search

Navigation