P55 the Treatment of Colesteryl Storage Disease (Cesd) by Ezetimibe Monotherapy

Abello, Francesca; Guardamagna, Ornella; Baracco, V.; Bonardi, R

doi:10.1016/s1567-5688(10)70122-7

Cited by 5 publications

(2 citation statements)

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“…There may, however, remain a subset of CESD patients who still require some form of adjunctive therapy for optimizing management of their dyslipidemia. In the literature on this subject, two case reports were found that focus on the use of ezetimibe, one as a monotherapy, the other in combination with lovastatin [50, 51]. Both involved patients in the second decade of life.…”

Section: Discussionmentioning

confidence: 99%

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Quantitation of the rates of hepatic and intestinal cholesterol synthesis in lysosomal acid lipase-deficient mice before and during treatment with ezetimibe

Chuang

Lopez

Turley

2017

Biochemical Pharmacology

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Esterified cholesterol (EC) and triglycerides, contained within lipoproteins taken up by cells, are hydrolysed by lysosomal acid lipase (LAL) in the late endosomal/lysosomal (E/L) compartment. The resulting unesterified cholesterol (UC) is transported via Niemann-Pick type C2 and C1 into the cytosolic compartment where it enters a putative pool of metabolically active cholesterol that is utilized in accordance with cellular needs. Loss-of-function mutations in LIPA, the gene encoding LAL, result in dramatic increases in tissue concentrations of EC, a hallmark feature of Wolman Disease and Cholesteryl Ester Storage Disease (CESD). The lysosomal sequestration of EC causes cells to respond to a perceived deficit of sterol by increasing their rate of cholesterol synthesis, particularly in the liver. A similar compensatory response occurs with treatments that disrupt the enterohepatic movement of cholesterol or bile acids. Here we measured rates of cholesterol synthesis in vivo in the liver and small intestine of a mouse model for CESD given the cholesterol absorption inhibitor ezetimibe from weaning until early adulthood. Consistent with previous findings, this treatment significantly reduced the amount of EC sequestered in the liver (from 132.43 ± 7.35 to 70.07 ± 6.04 mg/organ) and small intestine (from 2.78 ± 0.21 to 1.34 ± 0.09 mg/organ) in the LAL-deficient mice even though their rates of hepatic and intestinal cholesterol synthesis were either comparable to, or exceeded those in matching untreated Lal−/− mice. These data reveal the role of intestinal cholesterol absorption in driving the expansion of tissue EC content and disease progression in LAL deficiency.

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Section: Discussionmentioning

confidence: 99%

“…Both involved patients in the second decade of life. Ezetimibe monotherapy improved the plasma lipid composition and reduced liver transaminase activities [51]. In the patient that had been on long-term lovastatin treatment, the co-administration of ezetimibe resulted in a further 16% reduction in the plasma LDL-cholesterol level [50].…”

Section: Discussionmentioning

confidence: 99%

Quantitation of the rates of hepatic and intestinal cholesterol synthesis in lysosomal acid lipase-deficient mice before and during treatment with ezetimibe

Chuang

Lopez

Turley

2017

Biochemical Pharmacology

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Lysosomal acid lipase deficiency – An under-recognized cause of dyslipidaemia and liver dysfunction

Reiner¹,

Guardamagna²,

Nair³

et al. 2014

Atherosclerosis

253

228

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Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. The age at onset and rate of progression vary greatly and this may relate to the nature of the underlying mutations. Patients presenting in infancy have the most rapidly progressive disease, developing signs and symptoms in the first weeks of life and rarely surviving beyond 6 months of age. Children and adults typically present with some combination of dyslipidaemia, hepatomegaly, elevated transaminases, and microvesicular hepatosteatosis on biopsy. Liver damage with progression to fibrosis, cirrhosis and liver failure occurs in a large proportion of patients. Elevated low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels are common features, and cardiovascular disease may manifest as early as childhood. Given that these clinical manifestations are shared with other cardiovascular, liver and metabolic diseases, it is not surprising that LAL-D is under-recognized in clinical practice. This article provides practical guidance to lipidologists, endocrinologists, cardiologists and hepatologists on how to recognize individuals with this life-limiting disease. A diagnostic algorithm is proposed with a view to achieving definitive diagnosis using a recently developed blood test for lysosomal acid lipase. Finally, current management options are reviewed in light of the ongoing development of enzyme replacement therapy with sebelipase alfa (Synageva BioPharma Corp., Lexington, MA, USA), a recombinant human lysosomal acid lipase enzyme.

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Lysosomal acid lipase deficiency: a form of non-obese fatty liver disease (NOFLD)

A-Kader

2017

Expert Review of Gastroenterology & Hepatology

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With the growing obesity epidemic, nonalcoholic fatty liver disease (NAFLD) is rapidly becoming one of the leading causes of liver disease worldwide. Although obesity is a main risk factor for the development of NAFLD, it can also develop in lean subjects and can be encountered in different clinical setting and in association with an array of genetic, metabolic, nutritional, infectious and drug-induced disorders. Areas covered: This article discusses causes of fatty liver in non-obese subjects focusing on Lysosomal acid lipase deficiency (LAL-D), a commonly overlooked disorder reviewing its prevalence, genetics, pathogenesis, clinical features, diagnosis and treatment. It will also review other causes of non-alcoholic fatty liver disease, which can be encountered in the absence of obesity and metabolic syndrome. Expert commentary: Although the prevalence of LAL-D has been estimated in the range of 1 in 40,000 and 1 in 300,000, this estimate is much more than the identified cases reported in the literature, which suggests that that the disease may be considerably under-diagnosed. There is a pressing need to educate clinicians about the disease, especially with the development of new promising therapeutic modalities.

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P55 the Treatment of Colesteryl Storage Disease (Cesd) by Ezetimibe Monotherapy

Cited by 5 publications

References 0 publications

Quantitation of the rates of hepatic and intestinal cholesterol synthesis in lysosomal acid lipase-deficient mice before and during treatment with ezetimibe

Quantitation of the rates of hepatic and intestinal cholesterol synthesis in lysosomal acid lipase-deficient mice before and during treatment with ezetimibe

Lysosomal acid lipase deficiency – An under-recognized cause of dyslipidaemia and liver dysfunction

Lysosomal acid lipase deficiency: a form of non-obese fatty liver disease (NOFLD)

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