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 two copies of an altered gene for the same trait, one from each parent. If an individual inherits one normal gene and one 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 altered gene and have an affected child is one in four (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 normal genes from both parents is 25%. The risk is the same for males and females.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same altered gene, which increases the risk to have children with a recessive genetic disorder.
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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