Lysosomal Acid Lipase Deficiency (LAL-D)

Lysosomal acid lipase deficiency (LAL-D) is a life-threatening disease with a defined spectrum of clinical manifestations that depends on the amount of residual LAL enzymatic activity.1 Historically, LAL-D is subdivided into Wolman disease (WD), a severe neonatal-onset form with an (untreated) average life expectancy of <4 months, and cholesteryl ester storage disease (CESD), a milder childhood-to-adulthood-onset form with varying lifespan depending on disease progression and associated comorbidities.1–4 WD patients display a near-complete absence (<1%) of LAL activity, whereas children and adults with CESD exhibit a residual LAL activity between 1% and 12%.4–6 The abnormal LAL activity leads to massive lysosomal accumulation of cholesteryl esters and triglycerides throughout the body.2

Establishing a LAL-D Diagnosis

In its most aggressive form, WD, LAL-D rapidly progresses into hepatomegaly, liver dysfunction and failure, adrenal calcifications, diarrhea, malnutrition, weight loss and ultimately death.2,7,8 Sadly, the violent progression characteristic of WD facilitates its diagnosis. However, milder CESD forms are often undiagnosed for prolonged periods, until patients present with progressive fatty liver disease, splenomegaly, atherogenic dyslipidemia and premature atherosclerosis.3 Moreover, the nonspecific nature of these presenting symptoms, which are commonly observed in other metabolic syndromes, means the disease is often overlooked. This is likely correlated with the low number of reported cases with a LAL-D diagnosis in comparison with its estimated genetic prevalence.3 Therefore, in order to prevent underdiagnosis of LAL-D, it is crucial to raise awareness among clinicians so that the disease is considered and the correct diagnosis can be established.

Once suspected, LAL-D can essentially be diagnosed by 2 different tests: measurement of LAL enzymatic activity and genetic sequencing of the LIPA gene.2,3,9 To aid the timely diagnosis of LAL-D, Reiner and colleagues have proposed a diagnostic algorithm based on their clinical experience using these 2 studies.2 The histopathological analysis of liver biopsies and radiological techniques can also be used to support the diagnosis of LAL-D, though such methods are not considered diagnostic per se.

Assessment of LAL Activity

LAL activity can be measured biochemically in cultured fibroblasts, peripheral leukocytes, or liver tissue using different lipase substrates.2,9 According to Bernstein and colleagues, who reviewed the findings in 135 reported CESD patients, enzymatic activities for peripheral leukocytes or cultured fibroblasts ranged from “undetectable” to 16% of normal LAL activity, with most patients exhibiting activity values between <1% and 10%.9 However, the substrates used in these assays, such as 4-nitrophenyl palmitate, were not specific for LAL and may react with other lipases, thereby precluding direct comparisons of the residual LAL activities among patients. Furthermore, due to assay variability, residual enzyme activity is not predictive of disease severity and cannot be compared from one lab to another. In 2012, Hamilton et al. published a new method to determine LAL activity in dried blood spots (DBS) using 4-methylumbelliferyl-palmitate as the enzyme substrate together with a highly specific inhibitor of LAL, Lalistat 2.10

With this method, LAL activity is calculated by comparing total lipase activity with and without the presence of Lalistat 2. DBS testing can distinguish normal individuals from CESD homozygotes and heterozygotes.10 Advantages of the DBS technique include small sample size (50 mL blood) and long-term sample stability at room temperature (87% activity remaining after 100 days), which facilitates the transport to testing facilities. DBS testing is also available in several academic and commercial labs worldwide and has been a powerful tool in screening programs and large population-based surveys.

Genetic Testing

Sequencing of the LIPA gene is necessary to characterize the underlying mutation in each LAL-D patient. The LIPA gene is localized to chromosome 10q23.2-q23.3 and, to date, over 120 mutation variants have been identified for WD and CESD phenotypes.11–14 Although most affected patients are homozygous or compound heterozygous for LIPA mutations, some patients may have intronic mutations that go undetected in routine genetic screening.2 Therefore, the easily accessible, accurate, and low-cost DBS assay is the favored screening tool in a suspected case and LIPA sequencing is only recommended in case of a positive DBS test.3

Read more about LAL-D testing.

Liver Biopsy and Hepatic Magnetic Resonance

Liver biopsy allows a detailed evaluation of hepatic abnormalities, but at the risk of procedure-related morbidity and mortality.15 Hence, liver biopsy is only recommended to support the diagnosis of LAL-D if the other non-invasive methods, i.e. DBS testing and LIPA sequencing, are inconclusive. The detection of microvesicular steatosis on a liver biopsy is not exclusive of LAL-D and other histological features are needed to confirm a diagnosis.16 Accordingly, Hůlková and Elleder reported a set of distinctive histopathological features that support the diagnosis of LAL-D in liver biopsies obtained from CESD patients.16 Using paraffin-embedded tissue samples, they detected the presence of luminal (cathepsin D) and membrane lysosomal markers [lysosomal-associated membrane protein (LAMP)1, LAMP2, and lysosomal integral membrane protein (LIMP)2] around lipid vacuoles. Other diagnostic traits included auto-fluorescent detection of ceroid induction in storage macrophages and the absence of lip pigment in hepatocytes.16

Hepatic magnetic resonance represents a noninvasive approach to characterize the hepatic lipid signature in LAL-D patients.17 Importantly, this method can be used not only to monitor disease progression but also treatment outcomes, providing a favorable alternative to repeated biopsy sampling. 


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

2. 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:

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. 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

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:

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:

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. Abramov A, Schorr S, Wolman M. Generalized xanthomatosis with calcified adrenals. AMA J Dis Child. 1956;91(3):282-286. doi:10.1001/archpedi.1956.02060020284010

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:

10. 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

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

12. 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

13. Anderson RA, Bryson GM, Parks JS. Lysosomal acid lipase mutations that determine phenotype in Wolman and cholesterol ester storage disease. Mol Genet Metab. 1999;68(3):333-345. doi:10.1006/mgme.1999.2904

14. Carter A, Brackley SM, Gao J, Mann JP. The global prevalence and genetic spectrum of lysosomal acid lipase deficiency: a rare condition that mimics NAFLD. J Hepatol. 2019;70(1):142-150. doi:10.1016/j.jhep.2018.09.028

15. 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:

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:

17. Thelwall PE, Smith FE, Leavitt MC, et al. Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: noninvasive identification and treatment monitoring by magnetic resonance. J Hepatol. 2013;59(3):543-549. doi:

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