Long-term efficacy and safety of ezetimibe 10 mg in patients with homozygous sitosterolemia: a 2-year, open-label extension study

Lütjohann, Dieter; Bergmann, Klaus von; Sirah, Waheeda; Macdonell, Geraldine; Johnson‐Levonas, Amy O.; Shah, Arvind; Lin, Jianxin; Sapre, Aditi; Musliner, Thomas

doi:10.1111/j.1742-1241.2008.01841.x

Cited by 56 publications

(30 citation statements)

References 36 publications

(47 reference statements)

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“…The possibility of this disorder should be considered in such a condition, especially if it is correlated to recessive inheritance and/or associated with splenomegaly. This is clinically important for the early treatment of this disorder with a diet low in plant sterols, bile acid-binding resins [19,20] and a new sterol absorption inhibitor, ezetimibe [21,22], which have been proved to improve the prognosis and then probably to decrease the risk of early mortality.…”

Section: Discussionmentioning

confidence: 99%

A Phytosterolemia Patient Presenting Exclusively with Macrothrombocytopenia and Stomatocytic Hemolysis

Wang

Jianying

et al. 2011

Acta Haematol

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Background: Phytosterolemia is a rare autosomal recessive lipid storage disease. It is caused by mutations of ABCG5 and ABCG8 genes and characterized by the increased plasma levels of plant sterols. The common clinical manifestations include tendon and tuberous xanthomas and premature coronary heart disease; it has occasionally been associated with hematologic abnormalities. Aims: We report a phytosterolemia patient presenting exclusively with macrothrombocytopenia and stomatocytic hemolysis and discuss its clinical significance. Case Report: The patient, aged 31 years, was born of a consanguineous marriage. He had epistaxis from childhood and underwent splenectomy because of thrombocytopenia, anemia and splenomegaly at the age of 9 years. His blood film showed prominent stomatocytes and macroplatelets. High performance liquid chromatography showed a grossly elevated level of phytosterols in the blood. The patient was confirmed to be a homozygote of missense mutation R419H in ABCG5. Conclusion: We describe a phytosterolemia patient whose clinical manifestations were macrothrombocytopenia, stomatocytic hemolysis and splenomegaly, without the common features of this disorder. Our results suggest that blood cells could be a target for the toxic effect of plasma plant sterols, which should be measured in patients with unexplained stomatocytosis and/or macrothrombocytopenia in order to determine if they have phytosterolemia.

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Section: Discussionmentioning

confidence: 99%

A Phytosterolemia Patient Presenting Exclusively with Macrothrombocytopenia and Stomatocytic Hemolysis

Wang

Jianying

et al. 2011

Acta Haematol

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“…Inhibition of intestinal sterol absorption with ezetimibe corrects the metabolic phenotypes of a mouse model of sitosterolemia (11). Similarly, ezetimibe has been shown to be effective at lowering plasma phytosterols and LDL cholesterol in sitosterolemic patients, but there are conflicting data on the regression of xanthomas (12)(13)(14).…”

Section: Abcg5mentioning

confidence: 99%

The ABCG5 ABCG8 Sterol Transporter Opposes the Development of Fatty Liver Disease and Loss of Glycemic Control Independently of Phytosterol Accumulation

Shu

Sabeva

Liu

et al. 2012

Journal of Biological Chemistry

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Background: G5G8 promotes elimination of cholesterol. Results: The absence of G5G8 accelerates the loss of glycemic control and exacerbates the development of steatosis. Conclusion: G5G8 mitigates the impact of a high fat diet on hepatic lipid accumulation and glucose intolerance. Significance: Increased G5G8 in insulin resistance may be an adaptive mechanism that opposes steatosis but increases the risk of cholesterol gallstones.

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“…Conventional drug treatment in combination with ezetimibe has been shown to be more efficacious than treatment without ezetimibe in reducing plasma plant sterols in sitosterolemia patients, particularly in those who are not responsive to conventional drugs [83][84][85]. Ezetimibe is a drug that inhibits intestinal cholesterol and sterol absorption by the NPC1L1 protein [86][87][88].…”

Section: Treatment Of Sitosterolemiamentioning

confidence: 99%

Hepatobiliary Transport in Health and Disease

Häussinger¹,

Keitel²,

Kubitz³

2012

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Bile salts, cholesterol and phosphatidylcholine are secreted across the canalicular membrane of hepatocytes into bile by ATP-binding cassette (ABC) transporters. Secretion of bile salts by ABCB11 is essential for bile flow and for absorption of lipids and fat-soluble vitamins. ABCG5 and ABCG8 eliminate excess cholesterol and sterols from the body by secreting them into bile. There are two mechanisms to protect the canalicular membrane from solubilization by bile salts; ABCB4 secretes phosphatidylcholine into bile to form mixed micelles with bile salts, and ATP8B1 maintains the canalicular membrane in a liquid-ordered state. Three different forms of progressive familial intrahepatic cholestasis (PFIC) disorders, PFIC1, PFIC2 and PFIC3, are caused by mutations in ATP8B1, ABCB11 and ABCB4, respectively. Sitosterolemia is caused by mutations in ABCG5 and ABCG8. This article reviews the physiological roles of these canalicular transporters, and the pathophysiological processes and clinical features associated with their mutations. KeywordsATP-binding cassette transporter; bile; canalicular membrane; cholestasis; cholesterol; P4 ATPase; phospholipids Secretion of bile by the liverThe liver produces bile, which is essential for the elimination of endogenous compounds and xenobiotics from the body, for the emulsification of fat and for the intestinal absorption of lipids and fat-soluble vitamins. Bile is secreted into the canaliculi, which are small channels formed by the apical membranes of adjacent hepatocytes. Active secretion of organic solutes into the bile canaliculi by hepatocytes creates an osmotic gradient that causes water and electrolytes to flow from hepatocytes into the bile canaliculi. From the canaliculi, hepatic bile flows into the bile ducts, then through the bile ducts into the gallbladder. During fasting, bile is stored in the gallbladder, where water and electrolytes are absorbed and the organic solutes become more concentrated in gallbladder bile. During feeding, in response to stimulation by cholecystokinin and secretin, bile flows from the gallbladder into the small intestine [1,2].Transporters located at the canalicular membrane efflux endogenous compounds (bile salts, phospholipids, cholesterol and bilirubin) and xenobiotics (drugs, carcinogens and their Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Defects in ABCB11, ABCB4 and ATP8B1 cause progressive familial intrahepatic cholestasis (PFIC), a heterogeneous group of rare, autosomal recessive liver diseases of childhood. The estimated incidence is between 1:50,000 and 1:100,000 births [5]. Defects in either ABCG5 or ABCG8 cause an extremely rare autosomal recessive disease, sitosterolemia; only 80-100 cases have been report...

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Long-term efficacy and safety of ezetimibe 10 mg in patients with homozygous sitosterolemia: a 2-year, open-label extension study

Abstract: In patients with homozygous sitoserolemia, long-term treatment with ezetimibe 10 mg/day for 2 years was effective in reducing plasma plant sterol concentrations with an overall favourable safety and tolerability profile.

Cited by 56 publications

References 36 publications

A Phytosterolemia Patient Presenting Exclusively with Macrothrombocytopenia and Stomatocytic Hemolysis

A Phytosterolemia Patient Presenting Exclusively with Macrothrombocytopenia and Stomatocytic Hemolysis

The ABCG5 ABCG8 Sterol Transporter Opposes the Development of Fatty Liver Disease and Loss of Glycemic Control Independently of Phytosterol Accumulation

Hepatobiliary Transport in Health and Disease

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