Lysosomal Acid Lipase Deficiency (LAL-D)

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Lysosomal acid lipase deficiency (LAL-D) is a life-threatening genetic metabolic disorder with a wide phenotypic spectrum, ranging from the severe, infantile-onset form known as Wolman disease (WD) to later-onset forms collectively known as cholesterol ester storage disease (CESD).1,2 It is triggered by abnormal mutations in the LIPA gene that lead to reduced or absent enzymatic activity of LAL. The amount of residual LAL function typically determines the severity of lysosomal acid lipase deficiency symptoms.1,2

Impaired LAL function precipitates the disruption of intralysosomal degradation of cholesteryl esters and triglycerides, which continuously accumulate throughout the body causing multi-organ damage.1,2 This impairment of cholesterol homeostasis prompts a cascade of downstream intracellular events that lead to general dyslipidemia characterized by upregulated levels of serum transaminases, total cholesterol, low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) cholesterols, as well as downregulated levels of high-density lipoprotein (HDL) cholesterols.3–5

A summary of overall LAL-D symptoms has been published by Reiner and colleagues, which comprises hepatomegaly, splenomegaly, diarrhea, abdominal and epigastric pain, vomiting, anemia, malabsorption, cholestasis, steatorrhea, poor growth, gallbladder dysfunction, coronary heart disease, aneurysm, stroke, adrenal calcifications, and esophageal varices.1 

Findings from liver biopsies of LAL-D patients, include a bright yellow-orange coloration, enlarged lipid-loaded hepatocytes and Kupffer cells, microvesicular steatosis, fibrosis and micronodular cirrhosis.1 Importantly, clinical manifestations can vary considerably between patients and several of the most common symptoms, namely dyslipidemia, hepatomegaly and liver damage are also shared by other cardiovascular, liver and metabolic diseases.1

Symptomatology of WD

Infants with WD typically present a highly acute clinical course of the disease that can manifest as early as the first day of life.2,6,7 Growth failure and gastrointestinal symptoms, such as vomiting, steatorrhea, diarrhea and abdominal distention, are frequent and prominent symptoms. 

Some cases only come to medical attention weeks or months after birth mainly due to failure to thrive.8,9 Massive, usually dramatic hepatosplenomegaly is common, and the primary cause of abdominal distention.1,6 While present, the degree of splenomegaly is relatively small compared to the degree of hepatomegaly.10 Malnutrition, wasting, abdominal and epigastric pain, diarrhea and weight loss are prompted by thickened bowel walls that result from the increased gastrointestinal lipid deposition in the core villi of the lamina propria, lacteal endothelium, smooth muscle, duodenum and bowel mucosa.11,12 Steatosis may progress to fatal liver failure.6 Another classic finding of WD is the presence of enlarged adrenal glands with punctate calcifications which lead to adrenal cortical insufficiency.6,7 

The prognosis of WD infants is very poor and these do not usually survive beyond the first year of life (median life expectancy of 3.7 months).7 The probability of a growth failure-exhibiting WD infant surviving part 12 months has been estimated in 0.038 (95% confidence interval: 0.000-0.112).7 The course of WD is extremely aggressive and the invariable outcome of death results from a combination of malnutrition, liver disease, and adrenal cortical insufficiency.6 Recently, enzyme replacement treatment (ERT) with sebelipase alfa was shown to extend the lifespan of patients with WD to 24 months.13 Sebelipase alfa-treated infants presented weight-for-age improvements along with decreased hepatosplenomegaly, anemia and gastrointestinal symptoms.

Symptomatology of CESD

Given the heterogeneity of the onset and clinical manifestations of CESD, its natural course is less well defined than that of WD. Symptoms are usually only evident in late childhood or adulthood and, in the absence of previous family history, the detection of the disease is often delayed and even incidental.2

The severity of CESD symptoms is typically determined by the amount of residual LAL activity (1% to 12%) and the age of onset, with children normally presenting a worse long-term progression than adults.2,14,15 CESD children and adults commonly have type IIa or type IIb hyperlipidemia.5,16,17

Liver disease is the most common manifestation and also the primary cause of death in CESD patients.18,19 Elevated serum levels of transaminases are early indicators of liver damage; however, values can vary greatly between patients.18 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.6,18–20 

Asymptomatic low grade liver injury may silently progress to cirrhosis in late adulthood.1 Liver disease can also lead to hepatocellular carcinoma, as well as hemorrhage-prone and life-threatening esophageal varices.21 In the comprehensive review of the findings in 135 reported CESD patients by Bernstein and colleagues, hepatomegaly and splenomegaly were observed in approximately 99% and 74% of all patients, with 73% of deaths attributed to liver failure.18 Organomegaly may be present for years until the disease is diagnosed.22 Splenomegaly may lead to secondary complications, such as thrombocytopenia and/or anemia.6,12 Severe CESD patients can also exhibit adrenal cortical insufficiency due to enlarged adrenal glands with punctate calcifications.18,20 Dyslipidemia has been associated with an accelerated atherosclerotic profile and increased risk of both premature cardiovascular disease and cerebrovascular accidents.18,23 Thus, atherosclerosis accounts for much of the morbidity associated with late-onset CESD. 

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. 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

4. 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.

5. 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

6. 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.

7. 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

8. 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

9. 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

10. vom Dahl S, Mengel E. Lysosomal storage diseases as differential diagnosis of hepatosplenomegaly. Best Pract Res Clin Gastroenterol. 2010;24(5):619-628. doi:10.1016/j.bpg.2010.09.001

11. 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

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. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. vom Dahl S, Harzer K, Rolfs A, et al. Hepatosplenomegalic lipidosis: what unless gaucher? adult cholesteryl ester storage  disease (CESD) with anemia, mesenteric lipodystrophy, increased plasma chitotriosidase activity and a homozygous lysosomal acid lipase -1 exon 8 splice junction mutation. J Hepatol. 1999;31(4):741-746. doi:10.1016/s0168-8278(99)80356-023.

23. 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

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

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