Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: Non-invasive identification and treatment monitoring by magnetic resonance

Peter E. Thelwall,Anthony G. Quinn,Wei Hu,Michael I. Trenell,David Canty,Roy Taylor,Fiona E. Smith,Andrew M. Blamire,Mark C. Leavitt,Joseph V. Rutkowski,Christian Thoma,Kieren G. Hollingsworth

doi:10.1016/j.jhep.2013.04.016

Peter E. Thelwall, Anthony G. Quinn + Show 10 more

Open Access

https://doi.org/10.1016/j.jhep.2013.04.016

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Abstract

Background & AimsLysosomal Acid Lipase (LAL) deficiency is a rare metabolic storage disease, caused by a marked reduction in activity of LAL, which leads to accumulation of cholesteryl esters (CE) and triglycerides (TG) in lysosomes in many tissues. We used 1H magnetic resonance (MR) spectroscopy to characterize the abnormalities in hepatic lipid content and composition in patients with LAL deficiency, and in ex vivo liver tissue from a LAL deficiency rat model. Secondly, we used MR spectroscopy to monitor the effects of an enzyme replacement therapy (ERT), sebelipase alfa (a recombinant human lysosomal acid lipase), on hepatic TG and CE content in the preclinical model.MethodsHuman studies employed cohorts of LAL-deficient patients and NAFLD subjects. Rat experimental groups comprised ex vivo liver samples of wild type, NAFLD, LAL-deficient, and LAL-deficient rats receiving 4 weeks of sebelipase alfa treatment. Hepatic 1H MR spectroscopy was performed using 3T (human) and 7T (preclinical) MRI scanners to quantify hepatic cholesterol and triglyceride content.ResultsCE accumulation was identified in LAL deficiency in both human and preclinical studies. A significant decrease in hepatic CE was observed in LAL-deficient rats following treatment with sebelipase alfa.ConclusionsWe demonstrate an entirely non-invasive method to identify and quantify the hepatic lipid signature associated with a rare genetic cause of fatty liver. The approach provides a more favorable alternative to repeated biopsy sampling for diagnosis and disease progression / treatment monitoring of patients with LAL deficiency and other disorders characterised by increased free cholesterol and/or cholesteryl esters.

Highlights

Lysosomal Acid Lipase (LAL) deficiency is a rare autosomal recessive lysosomal storage disease for which there is no currently available effective treatment
We conclude that LAL deficiency is associated with distinct 1H and 13C MR signatures arising from cholesterol moieties, and that the 1H signature can be used to identify and quantify abnormal lipid substrate content in patients with LAL deficiency via this non-invasive method
Data from the preclinical 1H spectroscopy studies mirrored findings from the human 1H spectra: the ratio of 1H spectral resonances from CH2 and CH3 groups was substantially altered in LAL deficiency compared to non-alcoholic fatty liver disease (NAFLD)

Summary

Introduction

Lysosomal Acid Lipase (LAL) deficiency is a rare autosomal recessive lysosomal storage disease for which there is no currently available effective treatment. Diagnosis of late onset disease requires a high index of clinical suspicion as the combination of elevated transaminases, fatty liver, and dyslipidemia is seen in patients with the much more common diagnosis of metabolic syndrome. In addition to providing a method to monitor the efficacy of therapies that target CE accumulation, the identification and non-invasive quantification of hepatic CE content may allow for the identification of patients with fatty liver who have increased CE content and may warrant consideration for diagnostic testing for LAL deficiency. With the recent progression of sebelipase alfa into clinical studies for patients with LAL deficiency [12,13,14], such an approach would allow the non-invasive assessment of the effects of enzyme replacement on lipid substrate accumulation in key tissues including the liver in this disease

Materials and methods

Results

Discussion

D Cholesterol ppm