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The differential diagnosis of Lysosomal Acid Lipase Deficiency (LAL-D) can be particularly challenging as presenting features are not pathognomonic and its symptoms are similar to those of other cardiovascular, liver and metabolic diseases.1 This can lead to misdiagnosis and, consequently, inadequate management. For example, 2 American and Portuguese studies investigated the prevalence of LAL-D and LIPA mutations in cohorts of familial hypercholesterolemia and dyslipidemia and identified previously undiagnosed cases of LAL-D in both.2,3 Clinical manifestations of an attenuated cholesteryl ester storage disease (CESD) profile are often only evident in late childhood or adulthood and, in the absence of previous family history, the diagnosis of LAL-D is frequently delayed.1 This can lead to significant hepatic dysfunction and serious comorbidity-associated repercussions owing to the lack of timely treatment.
The low number of reported cases with a LAL-D diagnosis compared to its estimated genetic prevalence attests to the current underdiagnosis of the disease.4 Therefore, it is crucial to raise awareness among clinicians so that LAL-D is suspected in particular clinical scenarios and is considered for diagnostic screening. The establishment of a proper early diagnosis of LAL-D is necessary for appropriate management.4
Scenarios of Differential Diagnosis
Common misdiagnoses of CESD patients include heterozygous familial hypercholesterolemia (HeFH), familial combined hyperlipidemia (FCH), polygenic hypercholesterolemia (PH), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and cryptogenic cirrhosis.5
HeFH, FCH and PH patients present elevated total cholesterol and low-density lipoprotein (LDL), along with decreased high-density lipoprotein (HDL), which is the abnormal lipid profile shared by people with LAL-D.5–8 However, the inheritance of HeFH, FCH and PH is autosomal dominant, contrary to LAL-D, which is autosomal recessive.5,9 A detailed analysis of family history/pedigree can distinguish between these disorders. In HeFH, the levels of total cholesterol, LDL and HDL are usually higher than in LAL-D, though these may sometimes overlap.5,6,10 Moreover, HeFH is caused by mutations in the genes encoding for low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin 9 (PCSK9), which account for 60% to 95% of autosomal dominant hypercholesterolemia.11 Liver disease and organomegaly are usually not observed in familial hypercholesterolemia.9
CESD cases manifesting extremely high levels of total cholesterol and LDL may resemble autosomal recessive hypercholesterolemia (ARH).12 In this scenario, the profiling of the causative mutation can be used for differential diagnosis, since ARH is caused by mutations in the LDLRAP1 gene.13
Hepatosplenomegaly is a common feature of lysosomal storage disorders, such as LAL-D, Gaucher disease (GD) and Niemann-Pick disease (NPD).14 While LAL-D presents a degree of splenomegaly relatively smaller compared to the degree of hepatomegaly, GD exhibits a contrasting dominant splenomegaly and a minor degree of hepatomegaly. GD also lacks the abnormal lipid profile and adrenal calcifications typical of LAL-D (the latter occurs predominantly in Wolman’s disease phenotype but also occasionally in CESD).9,15 In turn, NPD and LAL-D share similar hepatosplenomegaly and lipid profiles.14 However, NPD causes interstitial lung disease and ophthalmologic findings that are absent in LAL-D. Furthermore, even though the inheritance of LAL-D, GD and NPD are autosomal recessive, causative mutations for these diseases are allocated to different genes, namely LIPA, GBA and SMPD1 (respectively).9,14,15
Other storage disorders related to hepatosplenomegaly include mucolipidosis II, mucopolysaccharidoses (MPS, types I, II, IVA and IVB) and glycogen storage diseases (GSD, types I, II, II, IV, V and VI).9 Here, LAL-D is distinguished by the absence of associated features, such as contractures and skeletal dysplasia in the case of mucolipidosis II and MPS and hypoglycemia, kidney disease and cardiomyopathy in the case of GSD.9
In CESD patients with dyslipidemia, hepatomegaly and persistently elevated serum transaminases, incorrect diagnoses may include NAFLD, NASH or cryptogenic liver disease.16 However, unlike LAL-D, these disorders are commonly associated with obesity, so body mass index should be a considered factor when analyzing the cause of “fatty liver” disease. Upon liver biopsy, microvesicular steatosis can be visualized in LAL-D, NAFLD, NASH and cryptogenic liver disease specimens.16 Hence, a method for distinctive histological diagnosis of CESD using paraffin-embedded tissue samples obtained from liver biopsies was developed by Hůlková and Elleder.17
The assessment is based on the immunostaining for lysosomal-associated membrane protein 1 (LAMP1), LAMP2 and lysosomal integral membrane protein 2 (LIMP2), as well as lysosomal luminal cathepsin D. These markers identify lysosomal lipid accumulation and facilitate the diagnosis of CESD, representing reliable histopathologic criteria that distinguishes CESD from other forms of microvesicular steatosis. While liver biopsy is not usually required for the diagnosis of LAL-D, these histopathological findings may be present in a liver biopsy performed to workup the more common NAFLD, NASH or cryptogenic liver disease.
To exclude more common disorders such as viral hepatitis and autoimmune liver disease, a full viral/immunological profile can be carried out, as suggested by Reiner and colleagues.5
1. 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
2. Chora JR, Alves AC, Medeiros AM, et al. Lysosomal acid lipase deficiency: a hidden disease among cohorts of familial hypercholesterolemia? J Clin Lipidol. 2017;11(2):477-484.e2. doi:10.1016/j.jacl.2016.11.002
3. Pullinger CR, Stock EO, Movsesyan I, et al. Identification and metabolic profiling of patients with lysosomal acid lipase deficiency. J Clin Lipidol. 2015;9(5):716-26.e1. doi:10.1016/j.jacl.2015.07.008
4. 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
5. 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
6. Gaddi A, Cicero AFG, Odoo FO, Poli AA, Paoletti R, Group A and MDS. Practical guidelines for familial combined hyperlipidemia diagnosis: an update. Vasc Health Risk Manag. 2007;3(6):877-886. https://pubmed.ncbi.nlm.nih.gov/18200807
7. 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
8. 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
9. 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.
10. Miltiadous G, Cariolou MA, Elisaf M. HDL cholesterol levels in patients with molecularly defined familial hypercholesterolemia. Ann Clin Lab Sci. 2002;32(1):50-54.
11. van der Graaf A, Avis HJ, Kusters DM, et al. Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. Circulation. 2011;123(11):1167-1173. doi:10.1161/CIRCULATIONAHA.110.979450
12. Stitziel NO, Fouchier SW, Sjouke B, et al. Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2013;33(12):2909-2914. doi:10.1161/ATVBAHA.113.302426
13. Garcia CK, Wilund K, Arca M, et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science. 2001;292(5520):1394-1398. doi:10.1126/science.1060458
14. 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
15. 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)80356-0
16. 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
17. 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
Reviewed by Michael Sapko, MD, on 7/1/2021.