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Sitosterinämie (Phytosterinämie)

Sitosterolemia (phytosterolemia)

  • Seltene Erkrankungen
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Zusammenfassung

Die Sitosterinämie oder Phytosterinämie ist eine seltene, autosomal-rezessiv vererbte Lipidspeichererkrankung. Sie wird verursacht durch homozygote oder komplex-heterozygote Mutationen in einem der beiden Gene ABCG5 und ABCG8, die für den intestinalen und hepatischen heterodimeren ABCG5(Sterolin-1)/ABCG8(Sterolin-2)-Effluxtransporter codieren. Diese Mutationen führen zu einer intestinalen Hyperabsorption und verminderten hepatischen Sekretion von Cholesterin und pflanzlichen Sterinen. Phytosterine finden sich hauptsächlich in pflanzlichen Ölen, Margarinen, Nüssen, Getreidekörnern, Sojabohnen und Avocados. Die Folgen einer Sitosterinämie sind Anhäufungen von Phytosterinen und Cholesterin im Plasma mit Ablagerung im Gewebe (Xanthome). Patienten mit Sitosterinämie zeigen eine extreme phänotypische Heterogenität von fast asymptomatischen Individuen bis zu solchen mit einer kombinierten ausgeprägten Hypercholesterinämie in jungen Jahren, die zu einer gesteigerten Atherosklerose und zum frühzeitigen kardialen Tod führt. Frühe Auffälligkeiten sind hämolytische Anämien mit Stomatozytose, Makrothrombozytopenie und Splenomegalie. Neben der strikten Vermeidung phytosterinhaltiger Nahrungsmittel stellt die Verabreichung des Sterinaufnahmehemmers Ezetimib eventuell in Kombination mit dem gallensäurebindenden Harz Colestyramin die effizienteste therapeutische Option dar.

Abstract

Sitosterolemia or phytosterolemia is a rare autosomal recessive hereditary lipid storage disorder. It is caused by homozygous or compound heterozygous mutations in one of the two ABCG5 and ABCG8 genes encoding the intestinal and hepatic heterodimer ABCG5 (sterolin 1)/ABCG8 (sterolin 2) efflux transporters. These mutations lead to intestinal hyperabsorption and reduced hepatic secretion of cholesterol and plant sterols with subsequent accumulation of phytosterols and cholesterol in plasma and deposition in tissue (xanthoma). Phytosterols are found mainly in vegetable oils, margarine, nuts, grains, soybeans and avocados. Patients with sitosterolemia show extreme phenotypic heterogeneity from almost asymptomatic individuals to those with combined severe hypercholesterolemia at a young age, leading to increased atherosclerosis and premature cardiac death. Early abnormalities include hemolytic anemia with stomatocytosis, macrothrombocytopenia and splenomegaly. In addition to strict avoidance of phytosterol-containing foods, the use of the sterol absorption inhibitor ezetimibe, possibly in combination with the bile acid-binding resin cholestyramine, is the most effective treatment option.

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Literatur

  1. Belamarich PF, Deckelbaum RJ, Starc TJ, Dobrin BE, Tint GS, Salen G (1990) Response to diet and cholestyramine in a patient with sitosterolemia. Pediatrics 86:977–981

    CAS  PubMed  Google Scholar 

  2. von Bergmann K, Sudhop T, Lütjohann D (2005) Cholesterol and plant sterol absorption: recent insights. Am J Cardiol 96:10D–14D

    Article  Google Scholar 

  3. Bhattacharyya AK, Connor WE (1974) Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest 53:1033–1043

    Article  CAS  Google Scholar 

  4. Bindl L, Lütjohann D, Buderus S, Lentze MJ, von Bergmann K (2000) High plasma levels of phytosterols in patients on parenteral nutrition: a marker of liver dysfunction. J Pediatr Gastroenterol Nutr 31:313–316

    Article  CAS  Google Scholar 

  5. Bindl L, Lütjohann D, Lentze MJ, von Bergmann K (2001) Cerebrotendinous xanthomatosis presenting as “chologenic diarrhoea”. Acta Paediatr 90:828–829

    CAS  PubMed  Google Scholar 

  6. Björkhem I (2013) Cerebrotendinous xanthomatosis. Curr Opin Lipidol 24:283–287

    Article  Google Scholar 

  7. Björkhem I, Muri-boberg K, Leitersdorf E (2001) Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol. In: Scriver C et al (Hrsg) The metabolic & molecular bases oh inherited disease, Bd. 2. McGraw-Hill, New York, S 2961–2988

    Google Scholar 

  8. Buchwald H (1964) Lowering of cholesterol absorption and blood levels by ileal exclusion. Experimental basis and preliminary clinical report. Circulation 29:713–720

    Article  CAS  Google Scholar 

  9. Buchwald H, Stoller DK, Campos CT, Matts JP, Varco RL (1990) Partial ileal bypass for hypercholesterolemia. 20- to 26-year follow-up of the first 57 consecutive cases. Ann Surg 212:318–329

    Article  CAS  Google Scholar 

  10. Chourdakis M, Buderus S, Dokoupil K, Oberhoffer R, Schwab KO, Wolf M, Zimmer K‑P, Koletzko B (2015) S2k-Leitlinien zur Diagnostik und Therapie von Hpyerlipidämien bei Kindern und Jugendlichen (Arbeitsgemeinschaft pädiatrischer Stoffwechselstörungen (APS) in der Deutschen Gesellschaft für Kinderheilkunde und Jugendmedizin e. V.)

    Google Scholar 

  11. Gregg RE, Connor WE, Lin DS, Brewer HB Jr. (1986) Abnormal metabolism of shellfish sterols in a patient with sitosterolemia and xanthomatosis. J Clin Invest 77:1864–1872

    Article  CAS  Google Scholar 

  12. Hansel B, Carrie A, Brun-Druc N, Leclert G, Chantepie S, Coiffard AS, Kahn JF, Chapman MJ, Bruckert E (2014) Premature atherosclerosis is not systematic in phytosterolemic patients: severe hypercholesterolemia as a confounding factor in five subjects. Atherosclerosis 234:162–168

    Article  CAS  Google Scholar 

  13. Izar MC, Tegani DM, Kasmas SH, Fonseca FA (2011) Phytosterols and phytosterolemia: gene-diet interactions. Genes Nutr 6:17–26

    Article  CAS  Google Scholar 

  14. Kanaji T, Kanaji S, Montgomery RR, Patel SB, Newman PJ (2013) Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia. Blood 122:2732–2742

    Article  CAS  Google Scholar 

  15. Kohse KP, Dörner K (2019) Taschenlehrbuch Klinische Chemie und Hämatologie, 9. Auflage. Georg Thieme Verlag, Stuttgart

    Google Scholar 

  16. Kwiterovich PO Jr., Bachorik PS, Smith HH, McKusick VA, Connor WE, Teng B, Sniderman AD (1981) Hyperapobetalipoproteinaemia in two families with xanthomas and phytosterolaemia. Lancet 1:466–469

    Article  CAS  Google Scholar 

  17. Lütjohann D, von Bergmann K (1997) Phytosterolaemia: diagnosis, characterization and therapeutical approaches. Ann Med 29:181–184

    Article  Google Scholar 

  18. Lütjohann D, von Bergmann K, Sirah W, Macdonell G, Johnson-Levonas AO, Shah A, Lin J, Sapre A, Musliner T (2008) 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 62:1499–1510

    Article  Google Scholar 

  19. Lütjohann D, Björkhem I, Beil UF, von Bergmann K (1995) Sterol absorption and sterol balance in phytosterolemia evaluated by deuterium-labeled sterols: effect of sitostanol treatment. J Lipid Res 36:1763–1773

    PubMed  Google Scholar 

  20. Lütjohann D, Björkhem I, Ose L (1996) Phytosterolaemia in a Norwegian family: diagnosis and characterization of the first Scandinavian case. Scand J Clin Lab Invest 56:229–240

    Article  Google Scholar 

  21. Mackay DS, Jones PJ, Myrie SB, Plat J, Lütjohann D (2014) Methodological considerations for the harmonization of non-cholesterol sterol bio-analysis. J Chromatogr B Analyt Technol Biomed Life Sci 957:116–122

    Article  CAS  Google Scholar 

  22. Mellies M, Glueck CJ, Sweeney C, Fallat RW, Tsang RC, Ishikawa TT (1976) Plasma and dietary phytosterols in children. Pediatrics 57:60–67

    CAS  PubMed  Google Scholar 

  23. Miettinen TA, Klett EL, Gylling H, Isoniemi H, Patel SB (2006) Liver transplantation in a patient with sitosterolemia and cirrhosis. Gastroenterology 130:542–547

    Article  Google Scholar 

  24. Nguyen LB, Shefer S, Salen G, Horak I, Tint GS, McNamara DJ (1988) The effect of abnormal plasma and cellular sterol content and composition on low density lipoprotein uptake and degradation by monocytes and lymphocytes in sitosterolemia with xanthomatosis. Metabolism 37:346–351

    Article  CAS  Google Scholar 

  25. Niu DM, Chong KW, Hsu JH, Wu TJ, Yu HC, Huang CH, Lo MY, Kwok CF, Kratz LE, Ho LT (2010) Clinical observations, molecular genetic analysis, and treatment of sitosterolemia in infants and children. J Inherit Metab Dis 33:437–443

    Article  CAS  Google Scholar 

  26. Oosterveer DM, Versmissen J, Yazdanpanah M, Hamza TH, Sijbrands EJ (2009) Differences in characteristics and risk of cardiovascular disease in familial hypercholesterolemia patients with and without tendon xanthomas: a systematic review and meta-analysis. Atherosclerosis 207:311–317

    Article  CAS  Google Scholar 

  27. Othman RA, Myrie SB, Mymin D, Merkens LS, Roullet JB, Steiner RD, Jones PJ (2015) Ezetimibe reduces plant sterol accumulation and favorably increases platelet count in sitosterolemia. J Pediatr 166:125–131

    Article  CAS  Google Scholar 

  28. Park JH, Chung IH, Kim DH, Choi MH, Garg A, Yoo EG (2014) Sitosterolemia presenting with severe hypercholesterolemia and intertriginous xanthomas in a breastfed infant: case report and brief review. J Clin Endocrinol Metab 99:1512–1518

    Article  CAS  Google Scholar 

  29. Parsons HG, Jamal R, Baylis B, Dias VC, Roncari D (1995) A marked and sustained reduction in LDL sterols by diet and cholestyramine in beta-sitosterolemia. Clin Invest Med 18:389–400

    CAS  PubMed  Google Scholar 

  30. Patel SB, Salen G, Hidaka H, Kwiterovich PO, Stalenhoef AF, Miettinen TA, Grundy SM, Lee MH, Rubenstein JS, Polymeropoulos MH, Brownstein MJ (1998) Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21. J Clin Invest 102:1041–1044

    Article  CAS  Google Scholar 

  31. Plat J, Baumgartner S, Vanmierlo T, Lütjohann D, Calkins KL, Burrin DG, Guthrie G, Thijs C, Te Velde AA, Vreugdenhil ACE, Sverdlov R, Garssen J, Wouters K, Trautwein EA, Wolfs TG, van Gorp C, Mulder MT, Riksen NP, Groen AK, Mensink RP (2019) Plant-based sterols and stanols in health & disease: “Consequences of human development in a plant-based environment?”. Prog Lipid Res 74:87–102

    Article  CAS  Google Scholar 

  32. Plat J, Brzezinka H, Lütjohann D, Mensink RP, von Bergmann K (2001) Oxidized plant sterols in human serum and lipid infusions as measured by combined gas-liquid chromatography-mass spectrometry. J Lipid Res 42:2030–2038

    CAS  PubMed  Google Scholar 

  33. Rees DC, Iolascon A, Carella M, O’Marcaigh AS, Kendra JR, Jowitt SN, Wales JK, Vora A, Makris M, Manning N, Nicolaou A, Fisher J, Mann A, Machin SJ, Clayton PT, Gasparini P, Stewart GW (2005) Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol 130:297–309

    Article  CAS  Google Scholar 

  34. Renner C, Connor WE, Steiner RD (2016) Sitosterolemia presenting as Pseudohomozygous familial Hypercholesterolemia. Clin Med Res 14:103–108

    Article  CAS  Google Scholar 

  35. Rios J, Stein E, Shendure J, Hobbs HH, Cohen JC (2010) Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia. Hum Mol Genet 19:4313–4318

    Article  CAS  Google Scholar 

  36. Sakuma N, Tada H, Mabuchi H, Hibino T, Kasuga H (2017) Lipoprotein Apheresis for Sitosterolemia. Ann Intern Med 167:896–899

    Article  Google Scholar 

  37. Salen G, Batta AK, Tint GS, Shefer S, Ness GC (1994) Inverse relationship between plasma cholestanol concentrations and bile acid synthesis in sitosterolemia. J Lipid Res 35:1878–1887

    CAS  PubMed  Google Scholar 

  38. Salen G, Kwiterovich PO Jr., Shefer S, Tint GS, Horak I, Shore V, Dayal B, Horak E (1985) Increased plasma cholestanol and 5 alpha-saturated plant sterol derivatives in subjects with sitosterolemia and xanthomatosis. J Lipid Res 26:203–209

    CAS  PubMed  Google Scholar 

  39. Silbernagel G, Chapman MJ, Genser B, Kleber ME, Fauler G, Scharnagl H, Grammer TB, Boehm BO, Makela KM, Kahonen M, Carmena R, Rietzschel ER, Bruckert E, Deanfield JE, Miettinen TA, Raitakari OT, Lehtimaki T, Marz W (2013) High intestinal cholesterol absorption is associated with cardiovascular disease and risk alleles in ABCG8 and ABO: evidence from the LURIC and YFS cohorts and from a meta-analysis. J Am Coll Cardiol 62:291–299

    Article  CAS  Google Scholar 

  40. Sudhop T, Lütjohann D, Kodal A, Igel M, Tribble DL, Shah S, Perevozskaya I, von Bergmann K (2002) Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation 106:1943–1948

    Article  CAS  Google Scholar 

  41. Tada H, Nohara A, Inazu A, Sakuma N, Mabuchi H, Kawashiri MA (2018) Sitosterolemia, Hypercholesterolemia, and coronary artery disease. J Atheroscler Thromb 25:783–789

    Article  CAS  Google Scholar 

  42. Teupser D, Baber R, Ceglarek U, Scholz M, Illig T, Gieger C, Holdt LM, Leichtle A, Greiser KH, Huster D, Linsel-Nitschke P, Schafer A, Braund PS, Tiret L, Stark K, Raaz-Schrauder D, Fiedler GM, Wilfert W, Beutner F, Gielen S, Grosshennig A, Konig IR, Lichtner P, Heid IM, Kluttig A, El Mokhtari NE, Rubin D, Ekici AB, Reis A, Garlichs CD, Hall AS, Matthes G, Wittekind C, Hengstenberg C, Cambien F, Schreiber S, Werdan K, Meitinger T, Loeffler M, Samani NJ, Erdmann J, Wichmann HE, Schunkert H, Thiery J (2010) Genetic regulation of serum phytosterol levels and risk of coronary artery disease. Circ Cardiovasc Genet 3:331–339

    Article  CAS  Google Scholar 

  43. Wang G, Wang Z, Liang J, Cao L, Bai X, Ruan C (2011) A phytosterolemia patient presenting exclusively with macrothrombocytopenia and stomatocytic hemolysis. Acta Haematol 126:95–98

    Article  Google Scholar 

  44. Wang J, Joy T, Mymin D, Frohlich J, Hegele RA (2004) Phenotypic heterogeneity of sitosterolemia. J Lipid Res 45:2361–2367

    Article  CAS  Google Scholar 

  45. Zaloga GP (2015) Phytosterols, lipid administration, and liver disease during Parenteral nutrition. Jpen J Parenter Enteral Nutr 39:39S–60S

    Article  Google Scholar 

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  1. Labor für spezielle Lipiddiagnostik, Institut für Klinische Chemie und Klinische Pharmakologie, Universitätsklinikum Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Deutschland

    D. Lütjohann

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Lütjohann, D. Sitosterinämie (Phytosterinämie). Internist 60, 871–877 (2019). https://doi.org/10.1007/s00108-019-0635-2

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