NORD gratefully acknowledges Semone Myrie, PhD, Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Canada; Jean-Baptiste Roullet, PhD, Clinical Professor, Department of Pharmacotherapy, College of Pharmacy, Washington State University, Spokane, WA; and the Sitosterolemia Foundation, for the preparation of this report.
Sitosterolemia is a rare genetic condition that causes the body to store plant sterols. There are at least two types of sterols: sterols from animals (example, cholesterol) and sterols from plants –also called phytosterols (example, sitosterol). Most people normally absorb plant sterols from the food they eat and excrete them in the gut. People with sitosterolemia absorb plant sterols but cannot excrete them, resulting in the accumulation of plant sterols in the body, especially in the blood and the arteries. Sitosterolemia is an autosomal recessive genetic condition caused by changes (mutations) in the ABCG5 or ABCG8 gene.
Standard lipid profiles do not check for plant sterol in the blood, so sitosterolemia is frequently missed unless a special blood test is ordered. Variability in presenting signs and symptoms and low awareness of this condition contribute to missed or delayed diagnosis. If left untreated, sitosterolemia can lead to premature hardening of the arteries (atherosclerosis) and premature death. However, sitosterolemia is manageable with medications that limit plant sterol absorption in the gut and with special diets that contain very little plant sterols.
Signs and symptoms of sitosterolemia vary from person to person, but any one of these symptoms alone is reason enough to be tested for it. Some patients (especially children) present with high cholesterol. While most cases of high cholesterol are not caused by sitosterolemia, if a patient’s cholesterol varies greatly with diet, but does not respond well to statins, then it could be a sign of sitosterolemia.
Patients with sitosterolemia may present with xanthomas, which are visible fatty deposits under the skin. They can be located anywhere, but frequently occur around the knees, heels, elbows, buttocks, or around the eyes. However, the absence of xanthomas should never be used to rule out sitosterolemia.
Deposits of plant sterols sometimes cause joint stiffness and pain. Some sitosterolemia patients only present with blood abnormalities such as low platelet count (thrombocytopenia), abnormally large platelets (macrothrombocytopenia) or abnormally shaped red blood cells (stomatocytes).
All sitosterolemia patients will have elevated levels of plant sterols in their blood (see Diagnosis section).
Sitosterolemia is an autosomal recessive genetic condition caused by mutations in the ABCG5 or ABCG8 gene.
Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
A recent report suggests that sitosterolemia has a global prevalence of at least 1 in 2.6 million for an ABCG5 gene mutation and 1 in 360,000 for an ABCG8 gene mutation [Hooper, et al, 2016]. The routine clinical test for measuring plasma concentration of cholesterol does not measure plant sterols; therefore sitosterolemia is likely to be underdiagnosed. Men and women are equally likely to have sitosterolemia, and anyone with this condition will have had it from birth, although many are not diagnosed until later.
Researchers identified one individual with sitosterolemia out of 2542 persons in whom plasma concentration of plant sterols was analyzed [Wilund et al 2004]. These researchers estimated a prevalence of 1/384 to 1/48,076.
Sitosterolemia has been described in various populations, including Hutterite, Amish, Japanese, Chinese, and Indian, as well as in other populations. High prevalence has been observed in the following populations:
• The Old Order Amish
• North American Hutterites
• The inhabitants of Kosrae (Micronesia)
Northern European/white individuals more frequently have mutations in the ABCG8 gene. Chinese, Japanese, and Indians tend to have mutations in the ABCG5 gene.
The diagnosis of sitosterolemia is established in individuals who have greatly increased plant sterol concentrations (especially sitosterol, campesterol, and stigmasterol) in the blood and tissues. Shellfish sterols can also be elevated.
Since standard lipid profiles do not test for the presence of plant sterols, a blood sample will have to be sent to a lab that uses specialized techniques such gas chromatography-mass spectrometry (GC-MS) or high pressure liquid chromatography (HPLC). A blood test that reveals frank elevation in phytosterol levels is considered diagnostic for sitosterolemia. Genetic testing for mutations in the ABCG8 and ABCG5 genes is available to confirm the diagnosis.
• In untreated individuals with sitosterolemia, the sitosterol concentration can be as high as 10 to 65 mg/dL. Plasma concentrations of sitosterol above 1 mg/dL are considered to be diagnostic of sitosterolemia (except in infants, in whom further testing may be necessary).
False-positive results have been observed in:
• Normal infants ingesting commercial infant formula (which contains plant sterols) may have a transient increase in plasma plant sterols.
• Patients with cholestasis or liver disease who are on parenteral nutrition (which contains plant sterols) may be unable to effectively clear the plant sterols.
• Carriers of only one gene mutation for sitosterolemia may occasionally have mildly elevated concentration of sitosterol (Note, however, that plasma concentrations of sitosterol are usually normal in carriers).
False-negative results can be observed in:
• Individuals using ezetimibe or ezetimibe combinations, or bile acid binding resin;
• Individuals on a diet low in plant-derived foods.
Clinical Testing and Work Up
Plasma concentrations of plant sterols (primarily sitosterol and campesterol) and cholesterol should be monitored, and the size, number, and distribution of xanthomas should be monitored at least every six to 12 months.
Platelet count should be monitored for thrombocytopenia, complete blood count (CBC) for evidence of hemolytic anemia, spleen for splenomegaly, and liver enzymes for elevation beginning at the time of diagnosis with the frequency determined by the severity of the clinical and biochemical findings.
Surveillance for atherosclerosis and coronary artery disease is suggested, with the level of monitoring determined by the severity of the clinical and biochemical findings.
Treatment aims to reduce plasma concentration of plant sterols to as close as possible to normal concentrations (i.e., <1 mg/dL), to control plasma concentration of cholesterol, and to prevent xanthoma formation and/or reduce the size and number of xanthomas. Current treatment therapies focus on the following:
Treatments should begin at the time of diagnosis. When tolerated, the combined treatments can decrease the plasma concentrations of cholesterol and sitosterol by 10% to 50%. Often existing xanthomas regress.
Arthritis, arthralgias, anemia, thromobocytopenia, and/or splenomegaly require treatment, the first step being management of the sitosterolemia, followed by routine management of the finding (by the appropriate consultants) as needed.
Sitosterolemia does not respond well to standard statin treatment.
Foods with high plant sterol content including shellfish, vegetable oils, margarine, nuts, avocados, and chocolate should be avoided or taken in moderation due to increased intestinal absorption of plant sterols in people with sitosterolemia.
Ezetimibe is the current standard of care for patients with sitosterolemia. Although ezetimibe lowers plant sterol levels in the blood of patients with sitosterolemia, it still remains very elevated; therefore ezetimibe therapy should be combined with other therapies to further reduce plant sterols levels. One study is currently testing the effect of a bile acid sequestrant such as colesevelam in combination with ezetimibe.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
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Hooper AJ, Bell DA, Hegele RA, Burnett JR. Clinical utility gene card for: Sitosterolaemia. European Journal of Human Genetics 2017;25, doi:10.1038/ejhg.2016.187; published online 28 December 2016. http://www.nature.com/ejhg/journal/v25/n4/full/ejhg2016187a.html
Yoo E-G. Sitosterolemia: a review and update of pathophysiology, clinical spectrum, diagnosis, and management. Ann Pediatr Endocrinol Metab. 2016 Mar; 21(1): 7–14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835564/
Kurvinen A, Nissinen MJ, Gylling H, Miettinen TA, Lampela H, Koivusalo AI, Rintala RJ, Pakarinen MP. Effects of long-term parenteral nutrition on serum lipids, plant sterols, cholesterol metabolism, and liver histology in pediatric intestinal failure. J Pediatr Gastroenterol Nutr. 2011;53:440–6. https://www.ncbi.nlm.nih.gov/pubmed/21543999
Niu DM, Chong KW, Hsu JH, Wu TJ, Yu HC, Huang CH, Lo MY, Kwok CF, Kratz LE, Ho LT. Clinical observations, molecular genetic analysis, and treatment of sitosterolemia in infants and children. J Inherit Metab Dis. 2010;33:437–43. https://www.ncbi.nlm.nih.gov/pubmed/20521169
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;17:891–900. https://www.ncbi.nlm.nih.gov/pubmed/20543520
Kidambi S, Patel SB. Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis. J Clin Pathol. 2008;61:588–94. https://www.ncbi.nlm.nih.gov/pubmed/18441155
Llop JM, Virgili N, Moreno-Villares JM, García-Peris P, Serrano T, Forga M, Solanich J, Pita AM. Phytosterolemia in parenteral nutrition patients: implications for liver disease development. Nutrition. 2008;24:1145–52. https://www.ncbi.nlm.nih.gov/pubmed/18656327
Lütjohann D, von Bergmann K, Sirah W, Macdonell G, Johnson-Levonas AO, 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;62:1499–510. https://www.ncbi.nlm.nih.gov/pubmed/18822021
Musliner T, Cselovszky D, Sirah W, McCrary Sisk C, Sapre A, Salen G, Lütjohann D, von Bergmann K. Efficacy and safety of ezetimibe 40 mg vs. ezetimibe 10 mg in the treatment of patients with homozygous sitosterolaemia. Int J Clin Pract. 2008;62:995–1000. https://www.ncbi.nlm.nih.gov/pubmed/18484971
Salen G, Starc T, Sisk CM, Patel SB. Intestinal cholesterol absorption inhibitor ezetimibe added to cholestyramine for sitosterolemia and xanthomatosis. Gastroenterology. 2006;130:1853–7. https://www.ncbi.nlm.nih.gov/pubmed/16697747
Salen G, von Bergmann K, Lütjohann D, Kwiterovich P, Kane J, Patel SB, Musliner T, Stein P, Musser B., Multicenter Sitosterolemia Study Group. Ezetimibe effectively reduces plasma plant sterols in patients with sitosterolemia. Circulation. 2004;109:966–71. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1237008/
Wilund KR, Yu L, Xu F, Vega GL, Grundy SM, Cohen JC, Hobbs HH. No association between plasma levels of plant sterols and atherosclerosis in mice and men. Arterioscler Thromb Vasc Biol. 2004;24:2326–32. https://www.ncbi.nlm.nih.gov/pubmed/15514206
Kwiterovich PO Jr, Chen SC, Virgil DG, Schweitzer A, Arnold DR, Kratz LE. Response of obligate heterozygotes for phytosterolemia to a low-fat diet and to a plant sterol ester dietary challenge. J Lipid Res. 2003;44:1143–55. https://www.ncbi.nlm.nih.gov/pubmed/12671028
Lu K, Lee MH, Hazard S, Brooks-Wilson A, Hidaka H, Kojima H, Ose L, Stalenhoef AF, Mietinnen T, Bjorkhem I, Bruckert E, Pandya A, Brewer HB Jr, Salen G, Dean M, Srivastava A, Patel SB. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1201544/
Lee MH, Lu K, Patel SB. Genetic basis of sitosterolemia. Curr Opin Lipidol. 2001;12:141–9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1350992/
Bindl L, Lütjohann D, Buderus S, Lentze MJ, v Bergmann K. High plasma levels of phytosterols in patients on parenteral nutrition: a marker of liver dysfunction. J Pediatr Gastroenterol Nutr. 2000;31:313–6. https://www.ncbi.nlm.nih.gov/pubmed/10997380
Mellies M, Glueck CJ, Sweeney C, Fallat RW, Tsang RC, Ishikawa TT. Plasma and dietary phytosterols in children. Pediatrics. 1976;57:60–7. https://www.ncbi.nlm.nih.gov/pubmed/946132
Bhattacharyya AK, Connor WE. Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest. 1974;53:1033–43. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC333088/
Myrie SB, Steiner RD, Mymin D. Sitosterolemia. 2013 Apr 4 [Updated 2020 Jul 16]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK131810/ Accessed April 5, 2021
Steiner R. Sitosterolemia. Medscape. Updated May 24, 2019. http://emedicine.medscape.com/article/948892-overview Accessed April 5, 2021.
Rare Diseases Clinical Research Network. Sterol & Isoprenoid Research Consortium.
http://www.rarediseasesnetwork.org/cms/stair/Learn-More/Disorder-Definitions Accessed April 5, 2021.
Sitosterolemia. Genetics Home Reference. Reviewed: November 2016 [updated August 18, 2020]. https://ghr.nlm.nih.gov/condition/sitosterolemia Accessed April 5, 2021.
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