Long term substrate reduction therapy with ezetimibe alone or associated with statins in three adult patients with lysosomal acid lipase deficiency

Abstract

BackgroundLysosomal acid lipase deficiency is an autosomal recessive metabolic disease with a wide range of severity from Wolman Disease to Cholesterol Ester Storage Disease. Recently enzyme replacement therapy with sebelipase alpha has been approved by drug agencies for treatment of this lysosomal disease.Ezetimibe is an azetidine derivative which blocks Niemann Pick C1-Like 1 Protein; as its consequence, plasmatic concentration of low density lipoproteins and other apoB-containing lipoproteins, that are the substrate of lysosomal acid lipase, are decreased. Furthermore, ezetimibe acts by blocking inflammasome activation which is the cause of liver fibrosis in steatohepatitis and in lysosomal storage diseases.ResultsTwo patients with Cholesterol Ester Storage Disease were treated with ezetimibe for 9 years and a third patients for 10 years. Treatment was supplemented with low dose of atorvastatin in the first two patients during the last 6 years. All patients showed a significant reduction of alanine aminotransferase, cholesterol and triglyceride. Furthermore, no progression of liver fibrosis was demonstrated.ConclusionIn this observational case series, ezetimibe is effective, safe, and sustainable treatment for lysosomal acid lipase deficiency. Further studies are warranted to demonstrate that ezetimibe is an alternative therapy to enzyme replacement therapy.

Lysosomal Acid Lipase: From Cellular Lipid Handler to Immunometabolic Target

“…However, in lal -/mice, ezetimibe significantly reduces the amount of CE sequestered in the liver and small intestine, thus improving liver steatosis and suggesting that intestinal cholesterol absorption could also play a role in cellular lipid accumulation observed in LAL-D [73]. In line with this, an amelioration of liver disease was observed in young CESD patients treated with ezetimibe alone or in association with statins [72,74,75].…”

“…Some reports indicate the use of ezetimibe in CESD patients, but robust data are not yet available on its lipid-lowering efficacy alone or in combination with statins [55,72]. However, in lal -/mice, ezetimibe significantly reduces the amount of CE sequestered in the liver and small intestine, thus improving liver steatosis and suggesting that intestinal cholesterol absorption could also play a role in cellular lipid accumulation observed in LAL-D [73].…”

<p>Lysosomal Acid Lipase Deficiency: Therapeutic Options</p>

“…Three patients with CESD, not on enzyme therapy, had been treated with ezetimibe for 9-10 years; this was supplemented with low dose atorvastatin in two patients during the last 6 years of observation. 34 All patients showed significant changes in their lipid profile, including a reduction of ALT, cholesterol and triglyceride. Furthermore, there was no demonstrable progression of liver fibrosis.…”

“…Furthermore, there was no demonstrable progression of liver fibrosis. 34 Although the use of lipid-lowering agents may be indicated to achieve an optimal outcome in patients with CESD, there may be other mechanisms of disease beyond those attributable to disruption of lipid metabolism associated with LAL deficiency that may be drivers of morbidity. Thus, close monitoring of patients on lipid-lowering agents will be necessary, so sebalipase alfa therapy can be initiated, if deemed appropriate.…”

Clinical outcome of a patient with lysosomal acid lipase deficiency and first results after initiation of treatment with Sebelipase alfa: A case report

“…Although hypercholesterolemia responds well to statins, this therapeutic option hardly has any effect on liver injury and progression of fibrosis. However, a recent case series of three young LALD patients showed a significant decrease in alanine aminotransferase (ALT) values and no further progression of liver fibrosis for up to ten years under treatment with ezetimibe [6]. Several patients with advanced liver disease, complications related to portal hypertension, and liver failure have undergone liver transplantation.…”