Lysosomal Acid Lipase Deficiency (LAL-D)


Lysosomal Acid Lipase Deficiency (LAL-D) disease is very rare, systemic and life limiting. LAL-D is characterized by functional mutations in the LIPA gene that result in abnormal enzymatic activity of LAL and subsequent continuous accumulation of cholesteryl esters and triglycerides throughout the body.1 It manifests in a wide spectrum of clinical manifestations, which range from severe infantile-onset form known as Wolman disease (WD) to milder progressive child-to-adulthood onset forms collectively known as cholesteryl ester storage disease (CESD).2

Cardinal clinical features include general dyslipidemia, hepatosplenomegaly, adrenal calcifications, as well as liver, gastrointestinal and vascular disease, which typically result in multi-organ damage and may lead to significant morbidity and premature mortality.1,2

An early differential diagnosis of LAL-D is fundamental to establish adequate treatment and control disease progression in view of avoiding serious comorbidity-associated complications.3

LAL-D Treatment Options

There are currently no specific disease treatments for LAL-D, but promising strategies are emerging. Until recently, existing approaches were primarily symptomatic and focused on supportive therapies to reduce the burden of disease complications.1,4

Possible treatment strategies are based on dietary manipulation, lipid-lowering drugs, hematopoietic stem cell transplantation (HSCT), liver transplantation and enzyme replacement therapy (ERT).1,4 Some of these approaches may be used in combination. In patients with advanced disease, additional procedures can be performed to limit morbidity, such as splenectomy and ligation of esophageal varices.4

Dietary Restrictions

Infants with WD usually manifest symptoms soon after birth, which typically involve vomiting, steatorrhea, diarrhea and abdominal distention, with subsequent malabsorption and growth failure.5,6 In 1985, clinical deterioration was slowed in an infant with WD after treatment with parenteral nutrition for 6 weeks.7 Diets free of hydrophobic esters were considered for WD infants; however, dietary manipulation did not improve their long-term survival.8

Some dietary precautions are still advised and consultation with a nutrition specialist is recommended, especially for the management of CESD.9,10 A low fat diet should be implemented in late-onset LAL-D patients and individuals with hepatic fibrosis should avoid excessive alcohol intake, while those with cirrhosis should avoid alcohol completely.9–11

Lipid-lowering Drugs

Prior to the availability of ERT, lipid-lowering drugs were frequently prescribed to LAL-D patients, particularly those with milder CESD phenotypes.1,12

Statins (HMG-CoA-reductase inhibitors) are low-density lipoprotein (LDL) cholesterol-lowering agents, which have been used either as monotherapy or in combination with other lipid-lowering drugs and found to reduce the lipid load and liver size in LAL-D patients.1,4,13 However, treatment success with statins has been mixed and, in some patients, the atherogenic lipid profile remains persistently elevated and disease progression remains unaffected.1–4,12 The disease stage at initiation of treatment with lipid-lowering drugs may have been a factor for continued disease progression.4

Other known lipid-lowering drugs that have been tested as monotherapies or in combination with statins in treatment of LAL-D consist of ezetimibe (a cholesterol absorption inhibitor) and cholestyramine (a bile acid sequestrant).1–4,14,15 These compounds were shown to induce significant changes in the lipid profile of patients, including decreased levels of total and LDL cholesterols.4,14,15

Hematopoietic Stem Cell and Liver Transplantation

HSCT has been performed in WD infants with mixed results and limited success in halting disease progression.16–20 Some studies report several procedure-related comorbidities.17,19

Liver transplant has also been undertaken in LAL-D patients, particularly those suffering from end-stage liver failure.4,21,22 Outcomes for severe cases of the disease have been dismal, with several reports of progressive deterioration despite transplant, acute rejection and transplant-related morbidity.4,21

The outcome of HSCT or liver transplantation following pretreatment or in combination with ERT remains to be investigated.4

Enzyme Replacement Therapy (ERT)

ERT envisages the reinstatement of enzymatic LAL activity in order to prevent the accumulation of cholesteryl esters and triglycerides and ultimately restore normal organ function.1,4 ERT has demonstrated significant improvements in the prognosis of LAL-D and is currently the preferred option to treat the disease.4 

The clinical use of sebelipase alfa (Kanuma©, Alexion Pharmaceuticals, Inc., Cheshire, CT, USA), a recombinant human LAL enzyme, was first reported by Balwani et al. in 2013.23 A comprehensive analysis of the clinical trials involving sebelipase-alfa can be found in the review of therapeutic options for LAL-D by Pastores and Hughes.4 Patients enrolled in clinical trials (LAL-CL01/LAL-CL04 and LAL-CL03) have presented significant improvements in liver function and the atherogenic lipid profile, with overall decreased levels of serum transaminases, total cholesterol, LDL and triglycerides.23–25 Remarkably, 56% of infants with WD from the pediatric study (LAL-CL03) survived to 24 months of age, well beyond the historical life expectancy for WD, exhibiting clear improvements in liver and gastrointestinal functions, as well as in overall growth.25

ERT has been demonstrated to be relatively safe and efficacious across a range of phenotypes, from WD to CESD.4 Importantly, an early diagnosis is essential to define a proper treatment strategy and increase the probability of success from ERT. Though the long-term clinical benefits of sebelipase alfa are still under evaluation, the favorable impact of its administration on disease course has brought hope to the dim prognosis of LAL-D. However, the cost of the ERT approach remains a major challenge in countries with limited healthcare resources.4,26

References

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. 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

3. 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

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. Browne M, Somers G, Savoia H, Kukuruzovic R. Wolman’s disease in an infant. Br J Haematol. 2003;122(4):522. doi:https://doi.org/10.1046/j.1365-2141.2003.04406.x

6. Shenoy P, Karegowda L, Sripathi S, Mohammed N. Wolman disease in an infant. BMJ Case Rep. 2014;2014:bcr2014203656. doi:10.1136/bcr-2014-203656

7. Meyers WF, Hoeg JM, Demosky SJ, Herbst JJ, Brewer HB. The use of parenteral hyperalimentation and elemental formula feeding in the treatment of wolman disease. Nutr Res. 1985;5(4):423-429. doi:https://doi.org/10.1016/S0271-5317(85)80226-8

8. Wolman M. Proposed treatment for infants with wolman disease. Pediatrics. 1989;83(6):1074-1075.

9. Kohli R, Ratziu V, Fiel MI, Waldmann E, Wilson DP, Balwani M. Initial assessment and ongoing monitoring of lysosomal acid lipase deficiency in  children and adults: consensus recommendations from an international collaborative working group. Mol Genet Metab. 2020;129(2):59-66. doi:10.1016/j.ymgme.2019.11.004

10. Hoffman EP, Barr ML, Giovanni MA, Murray MF. Lysosomal Acid Lipase Deficiency. 2015 Jul 30 [updated 2016 Sep 1]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021.

11. O’Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Hepatology. 2010;51(1):307-328. doi:10.1002/hep.23258

12. 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

13. Ginsberg HN, Le NA, Short MP, Ramakrishnan R, Desnick RJ. Suppression of apolipoprotein b production during treatment of cholesteryl ester storage disease with lovastatin. Implications for regulation of apolipoprotein b synthesis. J Clin Invest. 1987;80(6):1692-1697. doi:10.1172/JCI113259

14. Abello F, Guardamagna O, Baracco V, Bonardi R. P55 the treatment of cholesteryl storage disease (cesd) by ezetimibe monotherapy Atheroscler Suppl. 2010;11(2):28. doi:https://doi.org/10.1016/S1567-5688(10)70122-7

15. McCoy E, Yokoyama S. Treatment of cholesteryl ester storage disease with combined cholestyramine and  lovastatin. Ann N Y Acad Sci. 1991;623:453-454. doi:10.1111/j.1749-6632.1991.tb43768.x

16. Stein J, Garty BZ, Dror Y, Fenig E, Zeigler M, Yaniv I. Successful treatment of wolman disease by unrelated umbilical cord blood  transplantation. Eur J Pediatr. 2007;166(7):663-666. doi:10.1007/s00431-006-0298-6

17. Tolar J, Petryk A, Khan K, et al. Long-term metabolic, endocrine, and neuropsychological outcome of hematopoietic cell  transplantation for wolman disease. Bone Marrow Transplant. 2009;43(1):21-27. doi:10.1038/bmt.2008.273

18. 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

19. 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

20. Krivit W, Peters C, Dusenbery K, et al. Wolman disease successfully treated by bone marrow transplantation. Bone Marrow Transplant. 2000;26(5):567-570. doi:10.1038/sj.bmt.1702557

21. 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.2018.03.010

22. Ferry GD, Whisennand HH, Finegold MJ, Alpert E, Glombicki A. Liver transplantation for cholesteryl ester storage disease. J Pediatr Gastroenterol Nutr. 1991;12(3):376-378. doi:10.1097/00005176-199104000-00016

23. Balwani M, Breen C, Enns GM, et al. Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease. Hepatology. 2013;58(3):950-957. doi:10.1002/hep.26289

24. Valayannopoulos V, Malinova V, Honzík T, et al. Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves  serum lipids in patients with lysosomal acid lipase deficiency. J Hepatol. 2014;61(5):1135-1142. doi:10.1016/j.jhep.2014.06.022

25. Jones SA, Rojas-Caro S, Quinn AG, et al. Survival in infants treated with sebelipase alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study. Orphanet J Rare Dis. 2017;12(1):25. doi:10.1186/s13023-017-0587-3

26. Wyatt K, Henley W, Anderson L, et al. The effectiveness and cost-effectiveness of enzyme and substrate replacement  therapies: a longitudinal cohort study of people with lysosomal storage disorders. Health Technol Assess. 2012;16(39):1-543. doi:10.3310/hta16390

Reviewed by Michael Sapko, MD, on 7/1/2021.

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