The long-term use of sebelipase alfa (Kanuma®), an enzyme replacement therapy (ERT), resulted in overall improvements for patients with lysosomal acid lipase deficiency (LAL-D) but with significant interpatient variability, according to an invited commentary published in the Journal of Pediatric Gastroenterology and Nutrition.

The commentary discusses the results and impact of a previously published study by Burton et al which investigated the use of sebelipase alfa in patients with LAL-D for up to 144 weeks.

“Burton et al demonstrate that in contrast to infantile disease, ERT is not universally beneficial in individuals with attenuated disease: though many individuals show improvement, many have persistent hepatitis, dyslipidemia, and histological evidence of disease progression despite ERT,” the commentary’s authors Alanna Strong, MD, PhD, and Can Ficicioglu, MD, PhD, said.

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Strong and Ficicioglu proposed a number of different factors that may be involved in patients’ variable responses, including the patient’s age and disease severity at diagnosis. Other factors may include differences in mannose-6-phosphate receptor kinetics and the degree of intra-lysosomal cholesterol load mainly due to the amount of fat and cholesterol in the diet.

Read more about sebelipase alfa for LAL-D

Several genetic factors could also play a role including polymorphisms related to low-density lipoprotein receptor kinematics, Niemann Pick C transporter efflux activity, SREBP and LXR pathway activity, and ABCA1 efflux kinetics. Variability in the activation in the hepatic inflammatory pathway may also be responsible for variations in ERT response as well as the differences in the progression of nonalcoholic steatosis to hepatitis and cirrhosis.

“Many questions regarding the efficacy of ERT in LAL-D remain, including the long-term clinical course for infants saved by ERT, the long-term benefit in individuals with mild disease, the ability of ERT to reduce the risk of hepatocellular carcinoma, the etiology of poor ERT response, and the benefit of ERT to survival relative to the effect on quality of life,” Strong and Ficicioglu added.

In the commentary, Strong and Ficicioglu discussed that it is hard to predict a patient’s individual response to ERT and that little data are available on the long-term effect of ERT on overall morbidity and mortality. They also mentioned the importance of early diagnosis for patients.

“We propose that enzymology for [LAL-D] be performed in any infant presenting with hepatomegaly, failure to thrive, diarrhea or adrenal insufficiency,” they said. “In the adult population, [LAL-D] should be on the differential of hepatomegaly, steatosis, and dyslipidemia.”


Strong A, Ficicioglu C. Lessons learned from the long-term use of enzyme replacement therapy in the treatment of lysosomal acid lipase deficiency. J Pediatr Gastroenterol Nutr. Published online May 16, 2022. doi:10.1097/MPG.0000000000003453