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Lipoprotein Apheresis for Sitosterolemia

Background: Sitosterolemia is a rare autosomal recessive disease whose key feature is the inability to diminish uptake in the gut of noncholesterol sterols, such as those of plants and shellfish, or to excrete noncholesterol sterols into the bile (1, 2). It is caused by mutations in the adenosine triphosphatebinding cassette subfamily G member 5 or member 8 (ABCG5 or ABCG8) gene (1). Approximately 100 cases have been reported (1). The clinical manifestations in homozygous sitosterolemic patients are similar to those in patients with homozygous familial hypercholesterolemia. However, the total serum cholesterol levels in patients with homozygous sitosterolemia vary markedly, ranging from normal to extremely high (1, 2). Lipoprotein apheresis is used to reduce the levels of lipoproteins containing apolipoprotein B in patients with homozygous familial hypercholesterolemia. To our knowledge, use of lipoprotein apheresis for sitosterolemia has not been reported. Objective: To describe the use of lipoprotein apheresis to treat a patient with sitosterolemia. Case Report: In 1996, we were consulted about a 16-year-old boy with conspicuous xanthomas and arthralgia. The patient had had xanthomas on the fingers, elbows, knees, and buttocks since age 5 years. Physical examination was normal except for the xanthomas and carpal tunnel syndrome. Serum biochemical tests and a peripheral blood test revealed no abnormalities. The total serum cholesterol level was 4.01 mmol/L (155 mg/dL), triglyceride level was 0.6 mmol/L (55 mg/dL), and high-density lipoprotein cholesterol level was 1.40 mmol/L (54 mg/dL). However, the sitosterol level was 71.7 g/mL (normal levels, 0.5 to 5.0 g/mL), leading to a diagnosis of sitosterolemia (Figure 1). Genetic analyses done in 2001 confirmed that the patient had homozygous adenosine triphosphatebinding cassette subfamily G member 5 (ABCG5) R389H mutations (3). The patient's father and sister (but not the patient) had rare double heterozygous mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) E32K and in the ABCG5 gene, indicating that the patient's family had combined mutations for familial hypercholesterolemia and sitosterolemia (4). Because diet therapy did not reduce the patient's serum sitosterol levels, therapy with lipoprotein apheresis using a dextran sulfate cellulose column was begun at age 17 years (5). Figure 1. Serum sitosterol and total cholesterol levels during long-term lipoprotein apheresis. We obtained serum sitosterol levels immediately before and after lipoprotein apheresis. The normal range of sitosterol levels is 0.5 to 5.0 g/mL. To convert cholesterol values to mmol/L, multiply by 0.0259. The patient's xanthomas began to improve after this therapy was initiated, and those that had been rigid softened. After 1 year of therapy, pain in the wrist, elbow, and knee joints associated with reddish xanthomas gradually resolved along with the redness. Carpal tunnel syndrome also resolved as the xanthomas improved. Colestimide, 3 g/d, was added in 2001 and then replaced with ezetimibe, 10 mg/d, in 2007, which caused the serum sitosterol levels to decrease but did not affect total serum cholesterol levels. The patient's xanthomas continued to improve with the combination of lipoprotein apheresis and medication therapy. When the patient was 23 years of age, we assessed the intimamedia thickness of the far wall of the distal common carotid arteries using ultrasonography. The maximum intimamedia thickness was 1.3 mm on the right and 1.2 mm on the left (normal,<1.1 mm) (Figure 2). Findings on ultrasonography obtained when the patient was 33 years of age were nearly unchanged except that the walls were irregular because of plaque. At age 36 years, ultrasonography findings were normal and the maximum thickness was 0.6 mm on the right and 0.9 mm on the left (Figure 2). Thickness decreased when we increased the volume of lipoprotein apheresis to 4.0 L per session once per week without increasing the medication dose. Figure 2. Intimal thickness of the far wall of the distal CCAs on B-mode ultrasonography. We increased the treated plasma volume from 3.5 to 4.0 L per session per week in August 2015 (arrow) at age 35 y. This change caused already formed plaques to substantially regress and led to a maximum intimal wall thickness of 0.9 mm for the left CCA and 0.6 mm for the right, which are normal values. CCA= common carotid artery. Discussion: We have treated this patient with lipoprotein apheresis for 20 years and more recently have combined this treatment with medication therapy. The patient has had no adverse effects due to this long-term treatment, which has resolved the severe arthralgia, substantially improved the xanthomas, and caused already formed plaques in the common carotid arteries to regress. The patient has lived a normal life with no events due to atherosclerotic disease. On the basis of this experience, we believe that clinicians with similar patients should consider treatment with a combination of lipoprotein apheresis and medication therapy.