Mechanism of Disease

In cells missing the vital LAL enzyme, upregulation of cholesterol synthesis resulting from cellular dysfunction leads to ongoing lysosomal accumulation1

LAL-D is characterized by Disrupted Cholesterol Metabolism and Intracellular Accumulation of Lipids Across Organ Systems1,3

 

Image adapted from Reiner Ž, et al. Atherosclerosis. 2014;235(1):21-30 and Grabowski G, et al. The Online Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw Hill;2012.

LAL-D LEADS TO PROGRESSIVE MULTISYSTEM ORGAN DAMAGE2

LAL-D is characterized by disrupted cholesterol metabolism and intracellular accumulation of lipids across organ systems2

Lipa Mutation1

Missing or decreased LAL enzyme1

Lysosomal accumulation of CE/TG1

Dysregulated lipid metabolism1

Systemic Manifestations
POSSIBLE/POTENTIAL CONSEQUENCes

Liver1,2

  • Hepatomegaly
  • Hepatic injury
  • ↑ ALT
  • ↑ AST

POSSIBLE/POTENTIAL CONSEQUENCes

  • Microvesicular or mixed steatosis
  • Fibrosis
  • Cirrhosis
  • Portal hypertension
  • Liver failure

HEART1,2

  • Dyslipidemia
  • ↑ LDL-C
  • ↓ HDL-C

POSSIBLE/POTENTIAL CONSEQUENCes

  • Accelerated atherosclerosis
  • Coronary artery disease
  • Stroke
  • Myocardial infarction

Spleen1,2,4

  • Splenomegaly

POSSIBLE/POTENTIAL CONSEQUENCes

  • Anemia
  • Thrombocytopenia
  • Risk of traumatic rupture and/or splenectomy

Intestine1,2

  • Intestinal lipid accumulation

POSSIBLE/POTENTIAL CONSEQUENCes

  • Abdominal pain
  • Malabsorption
  • Growth failure

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CE/TG, cholesteryl ester/triglyceride; FC, free cholesterol; FFA, free fatty acid; HDL-C, high-density lipoprotein cholesterol; LAL-D, lysosomal acid lipase deficiency; LDL-C, low-density lipoprotein cholesterol; LDL-R, low-density lipoprotein cholesterol receptor; VLDL-C, very low-density lipoprotein cholesterol.

References: 1. Reiner Ž, et al. Atherosclerosis. 2014;235(1):21-30. 2. Bernstein DL, et al. J Hepatol. 2013;58(6):1230-1243. 3. Grabowski G, et al. The Online Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw Hill; 2012. 4. Radhakrishnan N. Splenomegaly. http://misc.medscape.com/pi/android/medscapeapp/html/A206208-business.html. Accessed November 14, 2020. 5. Lukacs Z, et al. Clinica Chimica Acta. 2017;471:201-205.

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