Lysosomal Acid Lipase Deficiency (LAL-D)

Lysosomal Acid Lipase Deficiency (LAL-D) is a multi-faceted rare genetic disorder with a wide spectrum of symptoms which severity and progression are based on the residual enzymatic activity of defective LAL, as well as on disease onset.^1,2 Cardinal clinical manifestations include a combination of general dyslipidemia and hepatic dysfunction that result from the massive lysosomal accumulation of cholesteryl esters and triglycerides, predominantly in the liver and in the vascular and reticuloendothelial systems.^1,3 

Atherosclerosis and liver disease associated comorbidities constitute the major cause of death in later-onset progressive forms of LAL-D collectively known as cholesterol ester storage disease (CESD).^1,2 Therefore, an early diagnosis of LAL-D is essential to provide proper management of the disease and limit morbidity-associated mortality. The recent development of a blood test to determine LAL activity provides physicians and other healthcare providers with a rapid method for detection of LAL-D.⁴ Specialists such as lipidologists, endocrinologists, cardiologists and hepatologists, who are more likely to be confronted with LAL-D cases in their clinical practice, must be aware of the hallmarks of the disease, as well as the available methods and guidelines for its differential diagnosis.

Specific therapeutic approaches to treat LAL-D, like hematopoietic stem cell transplantation (HSCT) and liver transplantation are also known to generate procedure-related morbidity.³ Liver biopsy to determine distinctive features of LAL-D encompasses another procedure with risk of morbidity and mortality, limiting its widespread application.^1,5

Dyslipidemia-related Morbidity

Dyslipidemia in LAL-D is characterized by general increased levels of serum transaminases, total cholesterol and low-density lipoprotein (LDL) cholesterols, as well as downregulated levels of high-density lipoprotein (HDL) cholesterols.^6–8 This abnormal lipid profile prompts accelerated atherosclerosis and premature cardio- and cerebrovascular disease.^9,10 In a study published in 1977, a child with CESD presented with aortic plaques, having died of portal hypertension at the age of 9 years.¹¹ In the review of the findings in 135 reported CESD patients, Bernstein and colleagues describe that hypercholesterolemia due to an increase in LDL cholesterol was present in nearly all patients, despite many of them being treated with statins, and that cardiovascular manifestations predominantly involved coronary artery disease, aneurysm and stroke.⁹ According to Strebinger et al., a comprehensive analysis of the cardiovascular outcome of CESD patients is still lacking and an international registry is currently being established.¹²

Although lipid-lowering agents, like sebelipase alfa, have been shown to produce significant improvements in the atherogenic lipid profile, with overall decreased levels of serum transaminases, total cholesterol, LDL and triglycerides, as well as increased levels of HDL, it is important to be aware of other possible disease mechanisms that may be drivers of morbidity, beyond those attributable to disruption of lipid metabolism.^3,13,14

Liver Disease-related Morbidity

Morbidities related to liver disease are recognized more frequently than vascular events in patients with LAL-D.¹ These include altered liver function, jaundice, steatosis, fibrosis, cirrhosis, hepatocellular carcinoma, hemorrhaging esophageal varices and multi-organ failure.^15–17 In their review, Bernstein and colleagues described that all 135 CESD patients suffered from liver dysfunction and/or failure, with 73% of reported deaths attributed to liver failure.⁹ Esophageal varices were observed in 8.9% of these subjects. Hepatosplenomegaly can lead to thrombocytopenia and/or anemia.^12,15 

The extent of liver disease-associated comorbidities will worsen in time without proper treatment, highlighting the urgent need for an early diagnosis. This was corroborated by a recently published study reporting a case of a 50 year-old female CESD patient who died with several sequelae of progressive liver disease after many years of mild symptoms without causal treatment.¹⁷ The patient was first diagnosed in 1979 by the age of 13 years, exhibiting marked hepatomegaly. Due to the lack of specific treatment at the time, the disease ran its course. In 2013, the patient presented with cirrhosis, esophageal varices (grade III) and hepatosplenomegaly with associated thrombocytopenia. In 2016, the patient was admitted with advanced liver disease, revealing compensated cirrhosis, highly hemorrhaging esophageal varices with vomiting of blood, followed by severe coagulopathy and hemorrhagic shock, having died after 2 weeks due to multi-organ failure.

Procedure-related Morbidity

HSCT has been attempted in a few infants with LAL-D but with mixed results and limited success.^18–22 In some cases, HSCT was associated with high toxicity, disease progression and fatal transplant-related complications.^19–21 In one child, treated with HSCT at 19 weeks of age, disease course was complicated by sinusoidal obstruction syndrome at 19 days post-procedure, with the child dying from multi-organ failure, coagulopathy and sepsis.¹⁹ In another child, transplanted at 19 months of age, sepsis and liver failure occurred at 14 days post-procedure.²¹

Prior to the existence of disease-specific enzyme therapy, liver transplant was considered the treatment of choice in patients with end-stage liver failure due to LAL-D.^3,23,24 However, Bernstein et al., investigated the outcome of 18 LAL-D patients who underwent liver transplantation and the results were underwhelming.²⁴ Multi-systemic disease progression still occurred in 61% of patients after the procedure. This is thought to derive from the fact that liver transplantation does not correct the main causative problem of the disease, which is a defective LAL activity that persists in other tissues. Thus, most patients exhibit hepatic recurrence after the transplanted liver is repopulated with recipient cells.²⁴ The outcome for patients with a more severe phenotype was the most reserved. Two sisters, diagnosed in infancy, had progressive deterioration after splenectomy and liver transplantation.²⁴ One of them presented intermittent episodes of acute rejection and post-mortem liver examination revealed progressive microvesicular steatosis, foamy macrophage aggregates, and vacuolated Kupffer cells, associated with advanced fibrosis and micronodular cirrhosis.

Liver biopsy is sometimes used to determine distinctive abnormal features of LAL-D, but has carries the risk of biopsy-related morbidity.^1,5 Therefore, its application should be carefully evaluated and current guidelines suggest that the procedure should only be performed if a diagnosis cannot be achieved using other non-invasive methods, such as a blood test for LAL activity and gene sequencing for LIPA.

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. Pastores GM, Hughes DA. Lysosomal acid lipase deficiency: therapeutic options. Drug Des Devel Ther. 2020;14:591-601. doi:10.2147/DDDT.S149264

4. Hamilton J, Jones I, Srivastava R, Galloway P. A new method for the measurement of lysosomal acid lipase in dried blood spots using  the inhibitor Lalistat 2. Clin Chim Acta. 2012;413(15-16):1207-1210. doi:10.1016/j.cca.2012.03.019

5. 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

6. Brown MS, Dana SE, Goldstein JL. Receptor-dependent hydrolysis of cholesteryl esters contained in plasma low density lipoprotein. Proc Natl Acad Sci U S A. 1975;72(8):2925-2929. doi:10.1073/pnas.72.8.2925

7. Goldstein JL, Dana SE, Faust JR, Beaudet AL, Brown MS. Role of lysosomal acid lipase in the metabolism of plasma low density lipoprotein. observations in cultured fibroblasts from a patient with cholesteryl ester storage disease. J Biol Chem. 1975;250(21):8487-8495.

8. Kostner GM, Hadorn B, Roscher A, Zechner R. Plasma lipids and lipoproteins of a patient with cholesteryl ester storage disease. J Inherit Metab Dis. 1985;8(1):9-12. doi:10.1007/BF01805475

9. 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

10. Elleder M, Ledvinová J, Cieslar P, Kuhn R. Subclinical course of cholesterol ester storage disease (CESD) diagnosed in adulthood. Virchows Arch A. 1990;416(4):357-365. doi:10.1007/BF01605297

11. Beaudet AL, Ferry GD, Nichols BLJ, Rosenberg HS. Cholesterol ester storage disease: clinical, biochemical, and pathological studies. J Pediatr. 1977;90(6):910-914. doi:10.1016/s0022-3476(77)80557-x

12. 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

13. 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

14. 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

15. 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.

16. Gasche C, Aslanidis C, Kain R, et al. A novel variant of lysosomal acid lipase in cholesteryl ester storage disease  associated with mild phenotype and improvement on lovastatin. J Hepatol. 1997;27(4):744-750. doi:10.1016/s0168-8278(97)80092-x

17. Canbay A, Müller MN, Philippou S, Gerken G, Tromm A. Cholesteryl ester storage disease: fatal outcome without causal therapy in a female patient with the preventable sequelae of progressive liver disease after many years of mild symptoms. Am J Case Rep. 2018;19:577-581. doi:10.12659/AJCR.907755

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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:10.1097/00005176-199104000-0001624.

24. 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

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

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Diogo Paramos, PhD

Biomedical Scientist, doctorate in Bioengineering. Determined to contribute to a world in which Healthcare and Innovation are accessible to everyone.