Sitosterolemia

Clinical characteristics: Sitosterolemia is characterized by: On occasion, the abnormal hematologic findings may be the initial presentation or the only clinical feature of this disorder. Arthritis, arthralgias, and splenomegaly may sometimes be seen and one study has concluded that "idiopathic" liver disease could be undiagnosed sitosterolemia. The clinical spectrum of sitosterolemia is probably not fully appreciated due to underdiagnosis and the fact that the phenotype in infants is likely to be highly dependent on diet.

Diagnosis/testing: In an individual with sitosterolemia, increased plasma concentrations of plant sterols (especially sitosterol, campesterol, and stigmasterol) are observed – if the diet includes plant-derived food, which contain plant sterols – once the plant sterols have accumulated in the body. The diagnosis of sitosterolemia is established in a proband with greatly increased plant sterol concentrations in plasma and/or by identification of biallelic pathogenic variants in ABCG5 and/or ABCG8.

Management: Treatment of manifestations: Treatment should begin at the time of diagnosis, though there is little experience treating children younger than age two years. Treatment can decrease plasma concentrations of cholesterol and sitosterol by 10% to 50%. Often existing xanthomas regress. Treatment recommendations include a diet low in shellfish sterols and plant sterols (vegetable oils, margarine, nuts, seeds, avocados, and chocolate) and use of the sterol absorption inhibitor, ezetimibe. In those with an incomplete response to ezetimibe, use of a bile acid sequestrant such as cholestryramine may be considered. Partial ileal bypass surgery may be considered as a last resort for those with poor response to maximal therapies. If arthritis, arthralgias, anemia, thrombocytopenia, and/or splenomegaly require treatment, the first step is management of the sitosterolemia, followed by routine symptomatic management. Surveillance: Begin monitoring at the time of diagnosis on an annual basis: plasma concentrations of plant sterols (primarily beta-sitosterol and campesterol) and cholesterol; the size, number, and distribution of xanthomas; and CBC and platelet count, and liver transaminases (for elevation). In persons with long-standing untreated sitosterolemia, noninvasive imaging is used to exclude coronary and carotid plaque as well as valvular atherosclerotic manifestations. Agents/circumstances to avoid: Margarines and other products containing stanols (e.g., campestanol and sitostanol) that are recommended for use by persons with hypercholesterolemia are contraindicated as they can exacerbate plant stanol accumulation. Evaluation of relatives at risk: Early diagnosis of at-risk relatives either through measurement of plasma concentrations of plant sterols or through molecular genetic testing (if the family-specific pathogenic variants are known) allows early institution of treatment and surveillance to optimize outcome. Pregnancy management: There are no adequate and well-controlled studies of ezetimibe in pregnant women; ezetimibe can be used during pregnancy only if the potential benefits justifiy the risk to the fetus. Since no studies have been published on the fetal effects of ezetimibe, it should be used with caution during pregnancy.

Genetic counseling: Sitosterolemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic but may occasionally have a mildly elevated concentration of sitosterol. Once the sitosterolemia-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.