Lysosomal Acid Lipase Deficiency (LAL-D)


Lysosomal acid lipase deficiency (LAL-D) is an ultra-rare life-limiting genetic disease caused by defects in LAL activity and insufficient lysosomal degradation of lipoproteins, predominantly cholesteryl esters and triglycerides.1 Lack of LAL activity results in accumulation of cholesterol derivatives in multiple cells throughout the body, mainly hepatocytes, vascular macrophages, and endothelial cells. This abnormal lipid profile leads to tissue dysfunction in key organ systems, particularly the liver, spleen, intestines, and the cardiovascular and cerebrovascular systems.1

The LIPA Gene

LAL-D is caused by mutations in the LIPA gene, which is localized to chromosome 10q23.2-q23.3.2 The gene consists of 10 exons, ranging in size from 39 to 1487 bp, and 9 introns. Various loss-of-function mutations in the LIPA gene have been identified in Wolman’s disease (WD) and cholesteryl ester storage disease (CESD) patients.3,4 The nature of the mutation and subsequent level of residual activity of the mutant LAL determines the severity of the disease.5,6 The most severe alterations in the LIPA gene (eg, nonsense mutations and frameshift defects) result in near-complete absence (<1%) of LAL activity and are associated with WD detected in infants.5–7 In contrast, less severe mutations lead to a residual (1% to 12%) LAL activity and occur in children and adults with CESD. The most common inherited defect in the LIPA gene, found in approximately 50% of CESD patients, is a splice site mutation in exon 8 (E8SJM; c.894G>A) that results in the deletion of the exon 8 in the mRNA.8

The Disruption of Cholesterol Homeostasis

A balanced cholesterol metabolism is essential for the maintenance of the phospholipid cell wall and preservation of cellular homeostasis. A defective LAL results in the entrapment of unhydrolyzed cholesteryl esters and triglycerides inside lysosomes, impairing the generation of free (unesterified) cholesterol derivatives and thereby reducing the feedback inhibition of β-hydroxy-β-methylglutaryl coenzyme A (HMG-CoA) reductase-mediated cholesterol biosynthesis.9,10 Increased HMG-CoA reductase activity promotes the upregulation of apolipoprotein (apo) B and low- and very-low-density cholesterol (LDL and VLDL), while downregulating the synthesis of high-density cholesterol (HDL), apo A1 and apo A2.9–11 Consequently, LAL-D patients exhibit a completely abnormal lipid profile, characterized by decreased plasma levels of HDL and increased plasma triglycerides and VLDL as well as upregulated LDL cholesterol and expression of LDL receptors on cell membranes.11,12

In a review of the findings in 135 CESD patients, Bernstein and colleagues described that total cholesterol and LDL cholesterol were significantly elevated in 100% and 95% of patients with reported values, respectively, while HDL cholesterol was significantly reduced in 89% of patients.3

LAL-D Clinical Manifestations 

The severity of LAL-D appears to be directly proportional to the magnitude of tissue build-up of cholesteryl esters and triglycerides and inversely proportional to the age of onset. Liver pathology is the most common manifestation and the primary cause of death in LAL-D patients.3,13 Massive lysosomal deposition of cholesteryl esters and triglycerides 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.3,13–15

In their review, Bernstein and colleagues described the occurrence of liver dysfunction and/or failure in all reported 135 CESD patients, with 73% of deaths attributed to liver failure.3 Liver disease can also lead to hepatocellular carcinoma and esophageal varices, which are highly prone to hemorrhaging.3,16 Individuals with dyslipidemia in the spleen often display splenomegaly and may develop anemia and thrombocytopenia as secondary complications.15,17

Gastrointestinal lipid deposition (eg, in the core villi of the lamina propria, lacteal endothelium, smooth muscle, duodenum, and bowel mucosa) leads to thickened bowel walls and subsequent malabsorption, abdominal and epigastric pain, diarrhea, and weight loss.17–19 Adrenal calcifications were reported to occur in both WD and severe CESD patients exhibiting enlarged adrenal glands and adrenal cortical insufficiency.3,14,15 Hyperlipidemia-associated atherosclerosis significantly increases the risk of cardiovascular and cerebrovascular accidents (namely coronary artery disease, aneurysm, and stroke) and is the major cause of morbidity related to late-onset CESD patients.3,17,20

While patients with CESD may have a normal lifespan depending on the severity of disease manifestations and treatment management, infants with WD do not usually survive beyond the first year of life and have a median life expectancy between 3 and 7 months.3,15,21 WD can manifest as early as the first day of life, with infant patients often exhibiting vomiting, chronic diarrhea or steatorrhea, abdominal distention, severe intestinal malabsorption, hepatic insufficiency and adrenal impairment.7,15,21 All these symptoms result in drastic loss of body weight and unavoidable failure to survive. Given their poor prognosis and short lifespan, it is unlikely that WD patients manifest accelerated atherosclerosis by the time of their death.

References

1. Reiner Ž, Guardamagna O, Nair D, et al. Lysosomal acid lipase deficiency – an under-recognized cause of dyslipidemia and liver dysfunction. Atherosclerosis. 2014;235(1):21-30. doi:https://doi.org/10.1016/j.atherosclerosis.2014.04.003

2. Anderson RA, Rao N, Byrum RS, et al. In situ localization of the genetic locus encoding the lysosomal acid lipase/cholesteryl esterase (LIPA) deficient in Wolman disease to chromosome 10q23.2-q23.3. Genomics. 1993;15(1):245-247. doi:https://doi.org/10.1006/geno.1993.1052

3. 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

4. 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 LIPA pathogenic variants. Atherosclerosis. 2017;265:124-132. doi:10.1016/j.atherosclerosis.2017.08.021

5. Saito S, Ohno K, Suzuki T, Sakuraba H. Structural bases of Wolman disease and cholesteryl ester storage disease. Mol Genet Metab. 2012;105(2):244-248. doi:https://doi.org/10.1016/j.ymgme.2011.11.004

6. Aslanidis C, Ries S, Fehringer P, Büchler C, Klima H, Schmitz G. Genetic and biochemical evidence that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity. Genomics. 1996;33(1):85-93. doi:https://doi.org/10.1006/geno.1996.0162

7. 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

8. Muntoni S, Wiebusch H, Jansen-Rust M, et al. Prevalence of cholesteryl ester storage disease. Arterioscler Thromb Vasc Biol. 2007;27(8):1866-1868. doi:10.1161/ATVBAHA.107.146639

9. 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

10. 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.

11. 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

12. Kelly DR, Hoeg JM, Demosky SJ, Brewer HB. Characterization of plasma lipids and lipoproteins in cholesteryl ester storage disease. Biochem Med. 1985;33(1):29-37. doi:https://doi.org/10.1016/0006-2944(85)90123-1

13. 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

14. 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

15. Hoffman EP, Barr ML, Giovanni MA, et al. Lysosomal acid lipase deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews® [Internet]. University of Washington, Seattle; 1993–2021. Published July 30, 2015. Updated September 1, 2016. Accessed July 2, 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. 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

18. Drebber U, Andersen M, Kasper HU, Lohse P, Stolte M, Dienes HP. Severe chronic diarrhea and weight loss in cholesteryl ester storage disease: a case report. World J Gastroenterol. 2005;11(15):2364-2366. doi:10.3748/wjg.v11.i15.2364

19. 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

20. 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

21. 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

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

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