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Lysosomal Acid Lipase Deficiency (LAL-D)

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Complications

Lysosomal acid lipase deficiency (LAL-D) is a rare inherited metabolic disorder, characterized by functional mutations in the LIPA gene that result in abnormal enzymatic activity of LAL and subsequent defective breakdown of body lipids.1

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 serious complications and premature mortality.1,2 Complications associated with atherosclerosis and liver disease constitute the major cause of death in later-onset progressive forms of LAL-D, collectively known as cholesterol ester storage disease (CESD).1,2 

In the early infantile-onset fulminant and lethal form of LAL-D, which is known as Wolman disease (WD), patients suffer from profound failure to grow/thrive due to a number of severe hepatic and gastrointestinal manifestations, which invariably lead to premature demise.1,2

To prevent comorbidity-associated complications, LAL-D needs to be diagnosed as soon as possible in order to provide proper treatment and control disease progression.3 Due to its multisystem nature and similarity of clinical manifestations to those of other cardiovascular, liver, and metabolic diseases, LAL-D is often misdiagnosed, prompting complications due to inadequate and untimely management.1,3

Growth Failure in WD Infants

Symptoms in WD infants usually manifest within days or weeks after birth and typically present a highly acute clinical course.2,4 Some cases only come to medical attention weeks or months after birth mainly due to failure to thrive, already presenting with severe complications and very reserved prognosis.5,6

A near-complete absence (<1%) of LAL activity results in massive lipid deposition in the core villi of the lamina propria, lacteal endothelium, smooth muscle, duodenum and bowel mucosa.7 This promotes a diffusely thickened bowel wall, leading to malnutrition, wasting, abdominal and epigastric pain, steatorrhea and diarrhea. In addition, infants with WD frequently present with vomiting and hepatosplenomegaly-associated abdominal distention.2,4 Consequently, patients exhibit profound growth failure with significant deficits in weight-for-age and height-for-age, not usually surviving beyond the first year of life (median life expectancy of 3.7 months).4 The probability of a growth failure-exhibiting WD infant surviving past 12 months has been estimated at 0.038 (95% confidence interval: 0.000-0.112).4

Cardiovascular and Cerebrovascular Complications

CESD children and adults commonly present with type IIa or type IIb hyperlipidemia.8–10 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.8,11,12 This abnormal lipid profile prompts accelerated atherosclerosis with increased risk of cardiovascular and cerebrovascular accidents.13,14 In a study published in 1977, 1 child with CESD presented with aortic plaques, having died of portal hypertension at the age of 9 years.15 In the comprehensive review of the findings in 135 reported CESD patients, Bernstein and colleagues describe that hypercholesterolemia 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.13

Continuous lysosomal lipid deposition in hepatocytes, Kupffer cells and other macrophages leads to hepatomegaly and diffuse microvesicular steatosis which, in time, progress to fibrosis, micronodular cirrhosis and, ultimately, liver failure.13,16–18 Bernstein et al. verified that hepatomegaly was present in approximately 99% of all patients, with 73% of deaths attributed to liver failure.13 Death due to liver disease progression occurred at 7 to 56 years of age, and 50% of deaths were in patients under 21 years of age. 

Liver disease can also lead to hepatocellular carcinoma and esophageal varices.19 In 2000, Elleder and colleagues reported a case of long-standing subclinical CESD in an individual who died at 52 years of age due a cholangiocarcinoma.20 In Bernstein et al., progression to esophageal varices was reported in 12 cases, including 9 from 5 to 20 years of age.13 

Splenomegaly may lead to secondary complications, such as thrombocytopenia and/or anemia.3,18

Enlarged adrenal glands with punctate calcifications can cause adrenal cortical insufficiency.13,17

Hematopoietic stem cell transplantation (HSCT), which has been tested in the treatment of LAL-D in view of providing a healthy source of LAL, has resulted in some cases of fatal post-procedure complications.21–23 In the case report by Yanir and colleagues, two siblings with WB treated with HSCT died from hepatic complications.21

Liver transplantation has been performed in patients with severe LAL-D. Success rates are low and have been associated with critical post-procedure complications such as acute rejection and progressive multi-systemic deterioration.24,25

There have also been reports of deadly cardiac complications during sebelipase alfa clinical studies, though these were deemed unlikely related to the study treatment.24,26

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. Jones SA, Valayannopoulos V, Schneider E, et al. Rapid progression and mortality of lysosomal acid lipase deficiency presenting in  infants. Genet Med. 2016;18(5):452-458. doi:10.1038/gim.2015.108

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. Nchimi A, Rausin L, Khamis J. Ultrasound appearance of bowel wall in Wolman’s disease. Pediatr Radiol. 2003;33(4):284-285. doi:10.1007/s00247-003-0873-1

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. Fouchier SW, Defesche JC. Lysosomal acid lipase A and the hypercholesterolaemic phenotype. Curr Opin Lipidol. 2013;24(4):332-338. doi:10.1097/MOL.0b013e328361f6c6

10. Zhang B, Porto AF. Cholesteryl ester storage disease: protean presentations of lysosomal acid lipase deficiency. J Pediatr Gastroenterol Nutr. 2013;56(6):682-685. doi:10.1097/MPG.0b013e31828b36ac

11. 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

12. 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.

13. 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

14. 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

15. 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

16. 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

17. Boldrini R, Devito R, Biselli R, Filocamo M, Bosman C. Wolman disease and cholesteryl ester storage disease diagnosed by histological and ultrastructural examination of intestinal and liver biopsy. Pathol – Res Pract. 2004;200(3):231-240. doi:https://doi.org/10.1016/j.prp.2003.11.001

18. 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.

19. 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

20. Elleder M, Chlumska A, Ledvinová J, Poupetová H. Testis – a novel storage site in human cholesteryl ester storage disease. Autopsy  report of an adult case with a long-standing subclinical course complicated by accelerated atherosclerosis and liver carcinoma. Virchows Arch. 2000;436(1):82-87. doi:10.1007/pl00008203

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. 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

23. Krivit W, Freese D, Chan KW, Kulkarni R. Wolman’s disease: a review of treatment with bone marrow transplantation and  considerations for the future. Bone Marrow Transplant. 1992;10 Suppl 1:97-101.

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

25. 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.2018.03.01026.

26. 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

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

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