Lysosomal acid lipase deficiency - early diagnosis is the key

Abstract

Lysosomal acid lipase deficiency (LAL-D) is an ultra-rare lysosomal storage disease that may present from infancy to late adulthood depending on residual enzyme activity. While the severe form manifests as a rapidly progressive disease with near universal mortality within the first 6 months of life, milder forms frequently go undiagnosed for prolonged periods and typically present with progressive fatty liver disease, enlarged spleen, atherogenic dyslipidemia and premature atherosclerosis. The adult variant of LAL-D is typically diagnosed late or even overlooked due to the unspecific nature of the presenting symptoms, which are similar to common changes observed in the context of the metabolic syndrome. This review is aimed at delineating clinically useful scenarios in which pediatric or adult medicine clinicians should be aware of LAL-D as a differential diagnosis for selected patients. This is particularly relevant as a potentially life-saving enzyme replacement therapy has become available and the diagnosis can easily be ruled out or confirmed using a dried blood spot test.

Keywords: atherogenic dyslipidemia; liver cirrhosis; low HDL; lysosomal acid lipase; microvesicular steatosis.

Figure 1

The clinical spectrum of LAL-deficiency. The clinical spectrum of LAL-deficiency ranges from severe variants with early death, previously referred to as Wolman disease, to milder variants manifesting during childhood or adulthood, known as CESD. Abbreviations: CESD, cholesteryl ester storage disease; LAL, lysosomal acid lipase; CE, cholesteryl esters; TG, triglycerides.

Figure 2

Summary of the mechanisms of disease. Cholesterol is physiologically taken up as cholesteryl esters via the LDL receptor – endocytosis pathway into lysosomes and then hydrolyzed by LAL enzyme (A). In cases of defective LAL activity cholesteryl esters and triglycerides accumulate in lysosomes, leading to universal microvesicular hepatic steatosis with development of fibrosis (C). Cholesterol accumulation causes orange coloration of the fatty liver (B), which is different from the triglyceride accumulation characteristic of common-type non-alcoholic fatty liver disease. (A) Published with permission of Alexion Pharmaceuticals. (B) and (C) Reproduced from Zandanell S, Primavesi F, Aigner E. Hepatosteatosis from Lysosomal Acid Lipase Deficiency. J Gastrointest Surg. 2019;23(3):601-602 (http://creativecommons.org/licenses/by/4.0/). Abbreviations: LAL, lysosomal acid lipase; CE, cholesteryl ester; TG, triglyceride; LAL, lysosomal acid lipase; LDL, low-density lipoprotein.

Figure 3

Development of the clinical manifestations in LAL-D. Although the mechanisms are universal as depicted in the sequence of events on the left, clinical manifestations and consequences range from liver disease to atherosclerosis and malabsorption. Abbreviations: LAL, lysosomal acid lipase; CE, cholesteryl esters; TG, triglycerides; ALT, aspartate transaminase; AST, alanine aminotransferase; LDL-c, low-density lipoprotein cholesterol; HDL-c, high-density lipoprotein cholesterol; ESLD, end-stage liver disease; MCI, myocardial infarction.

Figure 4

Hepatosplenomegaly. In LAL-D, the relative degree of hepatomegaly is usually prevalent over the relative degree of splenomegaly. The exclusion of hematological disorders should prompt the work-up for inherited storage disorders. Abbreviation: LAL-D, lysosomal acid lipase deficiency.

Figure 5

Vacuolated lymphocyte. Vacuolated lymphocytes may provide a diagnostic clue in many but not all lysosomal storage disorders. Although not massive in LAL-D, the presence of vacuolated lymphocytes can provide important diagnostic hints toward an underlying lysosomal storage disorder. Abbreviation: LAL-D, lysosomal acid lipase deficiency.