Biomedical Scientist, doctorate in Bioengineering. Determined to contribute to a world in which Healthcare and Innovation are accessible to everyone.
Lysosomal acid lipase deficiency (LAL-D) is a rare inherited autosomal recessive metabolic disorder characterized by a defective breakdown of body lipids.1 It is caused by abnormal mutations in the LIPA gene that result in reduced or absent enzymatic function, precipitating the disruption of intralysosomal degradation of cholesteryl esters and triglycerides, ultimately leading to their continuous accumulation in the liver, spleen, and other organ systems.2,3
Clinical hallmarks of LAL-D include hepatic dysfunction, dyslipidemia, and atherosclerosis that, as the pathology progresses, increase the risk of cardiovascular and cerebrovascular accidents.4 The disease can manifest itself in its most aggressive form during early infancy, with associated mortality within the first months of life, or in a less severe spectrum that can begin from childhood to late adulthood.2,5 For the latter, an early diagnosis and treatment are critical to halt disease progression, decrease comorbidities and extend the lifespan of patients.4
History of Lysosomal Acid Lipase Deficiency
LAL-D was first described by Wolman and colleagues in 1956.6 In this case report, a 2-month-old girl exhibiting massive bilateral calcification of the adrenal glands was admitted to Hadassah University Hospital in Israel in a very ill state which, despite treatment, rapidly deteriorated; the patient died on the third day of hospitalization. The autopsy revealed high amounts of a golden-yellowish fluid widespread throughout the abdomen and microscopic examination exposed a completely abnormal liver architecture and extensive lipidosis. The event was classified as a case of generalized xanthomatosis.
In 1965, the first 3 infant patients of American origin were reported to show similar symptoms to those described by Wolman, namely systemic cholesterol deposition, adrenal calcification, and death by 2-4 months of age.7 Since then, the term Wolman’s disease gained the favor of the medical community to classify severe LAL-D. In 1966, Japan announced its first cases of Wolman’s disease, while the first case in Scandinavia was published in 1992.8,9
In 1963, Frederickson presented a case study of a 12-year-old boy with an enlarged hypercholesterolemic liver containing 300 to 500 times the normal amount of cholesteryl esters.10 Over the years, cases with similar but less severe symptoms to those of Wolman’s disease were described in older patients across the globe.11 This later-onset condition was historically named cholesteryl ester storage disease (CESD).
Diagnosis, Treatment, and Management of LAL-D
Wolman’s disease and CESD share the same underlying molecular pathology and are considered early-onset and late-onset versions of the same disease. This difference is thought to be related to the nature of LIPA gene mutations and the resulting degree of residual LAL activity.11 It is unclear how other contributing factors (eg, environmental) can influence disease progression. While patients with Wolman’s disease exhibit <1% of normal LAL activity, CESD patients typically present residual LAL activity between 1% and 12%.11 The later age of onset and slightly less severe phenotype of CESD may reflect the residual LAL enzyme activity. Moreover, a number of abnormalities identified in CESD patients overlap with other disorders, such as familial combined hyperlipidemia or non-alcoholic fatty liver disease.11 For these reasons, cases are often undiagnosed or misdiagnosed, resulting in a shortage of clinical data that is paramount not only for a detailed understanding of the overall prognosis and life expectancy of LAL-D patients but also to determine the true frequency of the disease in the general population.
Methods for diagnosing LAL-D include blood testing for LAL activity, genetic testing for LIPA mutations, and liver biopsy for histopathological analysis of hepatic abnormalities.1 Though regarded as the most reliable method, the risks and costs of the liver biopsy procedure have limited its widespread application.13 Alternatively, hepatic magnetic resonance imaging can be used as a noninvasive method to assess lipid signatures in the liver and provide the means for a safe diagnosis and treatment monitoring of LAL-D.14
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Current treatment strategies for LAL-D patients mostly rely on supportive therapies to reduce the burden of disease complications, improve patients’ quality of life, and, if possible, extend their lifespan.1,4 Until recently, therapeutic approaches commonly consisted of dietary restrictions and cholesterol-lowering drugs, such as statins, bile acid sequestrants, and plant stanols.4 Hematopoietic stem cell and liver transplantation have also been undertaken in LAL-D patients.1,4 The former has been applied in infants with severe Wolman’s disease but has had limited success due to toxicity and engraftment issues.15,16 In turn, liver transplantation has been mostly unsuccessful in halting disease progression and also associated with several post-surgery complications like acute rejection, advanced fibrosis, and micronodular cirrhosis, demonstrating the inadequacy of the procedure.4,17
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Enzyme replacement therapy, which aims at reinstating the near-physiological levels of LAL, currently stands as one of the most promising strategies to treat LAL-D.18 Clinical trials for the safety and efficacy of sebelipase alfa, a recombinant human LAL, have been ongoing since 2013.4 Even though the long-term clinical benefits of sebelipase alfa in LAL-D patients still remain to be elucidated, observations from the ongoing studies have revealed increased survival of infants with Wolman’s disease, as well as significant improvements in liver function and the atherogenic lipid profile in both children and adult patients. Such beneficial outcomes indicate a favorable impact on disease course, highlighting the therapeutic potential of sebelipase alfa.
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1. Reiner Ž, Guardamagna O, Nair D, et al. Lysosomal acid lipase deficiency – an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis. 2014;235(1):21-30. doi:https://doi.org/10.1016/j.atherosclerosis.2014.04.003
2. Bernstein DL, Hülkova H, Bialer MG, Desnick RJ. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013;58(6):1230-1243. doi:https://doi.org/10.1016/j.jhep.2013.02.014
3. Pisciotta L, Tozzi G, Travaglini L, et al. Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel <em>LIPA</em> pathogenic variants. Atherosclerosis. 2017;265:124-132. doi:10.1016/j.atherosclerosis.2017.08.021
4. Pastores GM, Hughes DA. Lysosomal acid lipase deficiency: therapeutic options. Drug Des Devel Ther. 2020;14:591-601. doi:10.2147/DDDT.S149264
5. Strebinger G, Müller E, Feldman A, Aigner E. Lysosomal acid lipase deficiency – early diagnosis is the key. Hepat Med. 2019;11:79-88. doi:10.2147/HMER.S201630
6. Abramov A, Schorr S, Wolman M. Generalized xanthomatosis with calcified adrenals. AMA J Dis Child. 1956;91(3):282-286. doi:10.1001/archpedi.1956.02060020284010
7. Crocker AC, Vawter GF, Neuhauser EBD, Rosowsky A. Wolman disease: three new patients with a recently described lipidosis. Pediatrics. 1965;35(4):627-640. http://pediatrics.aappublications.org/content/35/4/627.abstract
8. Konno T, Fujii M, Watanuki T, Koizumi K. Wolman’s disease: the first case in Japan. Tohoku J Exp Med. 1966;90(4):375-389. doi:10.1620/tjem.90.375
9. Röyttä M, Fagerlund AS, Toikkanen S, et al. Wolman disease: morphological, clinical and genetic studies on the first Scandinavian cases. Clin Genet. 1992;42(1):1-7. doi:https://doi.org/10.1111/j.1399-0004.1992.tb03125.x
10. Fredrickson DS. Newly recognized disorders of cholesterol metabolism. Ann Intern Med. 1963;58(4):718. doi:10.7326/0003-4819-58-4-718_1
11. Pericleous M, Kelly C, Wang T, Livingstone C, Ala A. Wolman’s disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency. Lancet Gastroenterol Hepatol. 2017;2(9):670-679. doi:10.1016/S2468-1253(17)30052-3
12. Hůlková H, Elleder M. Distinctive histopathological features that support a diagnosis of cholesterol ester storage disease in liver biopsy specimens. Histopathology. 2012;60(7):1107-1113. doi:https://doi.org/10.1111/j.1365-2559.2011.04164.x
13. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005-2023. doi:https://doi.org/10.1002/hep.25762
14. Thelwall PE, Smith FE, Leavitt MC, et al. Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: non-invasive identification and treatment monitoring by magnetic resonance. J Hepatol. 2013;59(3):543-549. doi:https://doi.org/10.1016/j.jhep.2013.04.016
15. Gramatges MM, Dvorak CC, Regula DP, Enns GM, Weinberg K, Agarwal R. Pathological evidence of Wolman’s disease following hematopoietic stem cell transplantation despite correction of lysosomal acid lipase activity. Bone Marrow Transplant. 2009;44(7):449-450. doi:10.1038/bmt.2009.57
16. Yanir A, Allatif MA, Weintraub M, Stepensky P. Unfavorable outcome of hematopoietic stem cell transplantation in two siblings with Wolman disease due to graft failure and hepatic complications. Mol Genet Metab. 2013;109(2):224-226. doi:https://doi.org/10.1016/j.ymgme.2013.03.007
17. Bernstein DL, Lobritto S, Iuga A, et al. Lysosomal acid lipase deficiency allograft recurrence and liver failure — clinical outcomes of 18 liver transplantation patients. Mol Genet Metab. 2018;124(1):11-19. doi:https://doi.org/10.1016/j.ymgme.2018.03.01018.
18. Grabowski G. Therapy for lysosomal acid lipase deficiency: replacing a missing link. Hepatology. 2013;58(3):850-852. doi:https://doi.org/10.1002/hep.26366
Reviewed by Michael Sapko, MD, on 7/1/2021.