Elsevier

Journal of Hepatology

Volume 59, Issue 3, September 2013, Pages 543-549
Journal of Hepatology

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

https://doi.org/10.1016/j.jhep.2013.04.016Get rights and content
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open access

Background & Aims

Lysosomal 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.

Methods

Human 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.

Results

CE 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.

Conclusions

We 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.

Abbreviations

CESD
cholesteryl ester storage disease
LAL
lysosomal acid lipase
CE
cholesteryl ester
TG
triglyceride
ERT
enzyme replacement therapy
NAFLD
non-alcoholic fatty liver disease

Keywords

Wolman disease
Cholesteryl ester storage disease
1H MR spectroscopy
13C MR spectroscopy
Liver fat
Lysosomal acid lipase
LIPA
LAL deficiency
Enzyme replacement therapy
Sebelipase alfa

Cited by (0)

These authors share a joint senior authorship.