Persistent dyslipidemia in treatment of lysosomal acid lipase deficiency

Abstract

Background: Lysosomal acid lipase deficiency (LALD) is an autosomal recessive inborn error of lipid metabolism characterized by impaired lysosomal hydrolysis and consequent accumulation of cholesteryl esters and triglycerides. The phenotypic spectrum is diverse, ranging from severe, neonatal onset failure to thrive, hepatomegaly, hepatic fibrosis, malabsorption and adrenal insufficiency to childhood-onset hyperlipidemia, hepatomegaly, and hepatic fibrosis. Sebelipase alfa enzyme replacement has been approved by the Food and Drug Administration for use in LALD after demonstrating dramatic improvement in transaminitis and dyslipidemia with initiation of enzyme replacement therapy. Methods: A chart review was performed on 2 patients with childhood-onset, symptomatic LALD with persistent dyslipidemia despite appropriate enzyme replacement therapy to identify biological pathways and risk factors for incomplete response to therapy. Results: Two patients with attenuated, symptomatic LALD had resolution of transaminitis on enzyme replacement therapy without concomitant effect on dyslipidemia despite dose escalation and no evidence of antibody response to enzyme. Conclusion: Enzyme replacement therapy does not universally resolve all complications of LALD. Persistent dyslipidemia remains a clinically significant issue, likely related to the complex metabolic pathways implicated in LALD pathogenesis. We discuss the possible mechanistic basis for this unexpected finding and the implications for curative LALD therapy.

Impaired Bile Acid Metabolism and Gut Dysbiosis in Mice Lacking Lysosomal Acid Lipase

“…In addition to hepatosplenomegaly and dyslipidemia (in 74-90% of patients), gastrointestinal symptoms such as malnutrition, cachexia, diarrhea, steatorrhea, and vomiting were described in 30% of 206 adult and pediatric patients [5,[7][8][9]. The approval of enzyme replacement therapy in 2015 dramatically changed the treatment strategy for LAL-D from supportive care to sustained improvement in the clinical outcomes, although with some therapeutic and significant pharmacoeconomic limitations [10].…”

Living-Donor Liver Transplantation for Late-Onset Lysosomal Acid Lipase Deficiency

“…Liver disease progresses due to enhanced acceleration of intracellular accumulation of cholesteryl ester (3,13). Sebelipase alfa, has shown beneficial effects on several in clinical outcomes in randomized controlled trials and the drug is currently approved for use in many countries ( 14) However, persistent dyslipidemia despite sebelipase alfa therapy in two LAL-D subjects has been reported in literature (15). This is likely related to the complex metabolic pathways implicated in LAL-D pathogenesis.…”

Hepatic Manifestations of Mendelian Disorders of Cholesterol Biosynthesis and Cellular Metabolism

“…Abbreviations: ABCA1, ATP-binding cassette transporter 1 APOA1, apolipoprotein A1; FC, free cholesterol; FFA, free fatty acids; HDL, high-density lipoprotein; LAL, lysosomal acid lipase; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; NPC1/2, Niemann-Pick C; VLDL, very-low density lipoprotein. 15 There is little to be done regarding the hepatic steatosis, but rarely is liver disease the predominant clinical consideration in these patients.…”

“…In LALD, LDL cannot be hydrolyzed to generate FC and FFAs, so cholesterol biosynthesis cannot be downregulated, there is less cholesterol available to efflux to HDL, and ABCA1 production cannot be stimulated. Abbreviations: ABCA1, ATP‐binding cassette transporter 1 APOA1, apolipoprotein A1; FC, free cholesterol; FFA, free fatty acids; HDL, high‐density lipoprotein; LAL, lysosomal acid lipase; LDL, low‐density lipoprotein; LDLR, low‐density lipoprotein receptor; NPC1/2, Niemann‐Pick C; VLDL, very‐low density lipoprotein 15 . Figure was adapted from Ref.…”