Lysosomal Acid Lipase Deficiency (LAL-D)


Lysosomal acid lipase deficiency (LAL-D) is an ultra-rare, systemic, autosomal recessive disorder, characterized by functional mutations in the LIPA gene that result in abnormal enzymatic activity of LAL and subsequent continuous accumulation of cholesteryl esters and triglycerides throughout the body.1

Key disease hallmarks include general dyslipidemia, hepatosplenomegaly, adrenal calcifications, as well as liver, gastrointestinal and vascular disease, which may lead to significant morbidity and premature mortality in some patients.1,2 Given the systemic nature of the disease, there is a wide range of healthcare specialists that may be confronted with LAL-D cases in their clinical practice. 

Therefore, healthcare providers must be aware not only of the available methods and guidelines for the assessment and differential diagnosis of LAL-D but also of the recommendations for its monitoring. In view of this, a collaborative group of internationally recognized healthcare specialists with relevant expertise (such as pathology, hepatology, gastroenterology, cardiology, and lipidology) have recently developed an evidence-based consensus of guideline recommendations for the initial assessment and ongoing monitoring of LAL-D.3

These guidelines are based on patient age and clinical manifestations regardless of treatment status and are designed to help improve the management of LAL-D patients. Importantly, they are intended to serve as a foundation for the assessment and monitoring of LAL-D but may need to be adapted to each individual patient depending on clinical manifestations and severity.

Initial Evaluation and Baseline Assessments

LAL-D can be primarily diagnosed by two different techniques: assessment of LAL activity in blood dried blood spots (DBS) and genetic sequencing of the LIPA gene for the identification of pathogenic mutations.1,4–6 LAL activity can also be measured in blood leukocytes and fibroblasts but DBS testing with a highly specific LAL inhibitor is currently the most reliable method.5,6 Genetic testing is only recommended in case of a positive biochemical DBS test.4 Residual LAL activity and genotyping provide limited information on prognosis and natural history in LAL-D.3

A comprehensive clinical evaluation comprising a detailed medical and family history should be documented.3 This includes age of onset and symptom manifestations, as well as physical examination for organomegaly and stigmata of liver disease (e.g., spider angiomas, jaundice). For children, a growth/developmental assessment (ie, weight and height for age) should also be performed. A screening for differential diagnosis should be carried out to exclude metabolic disorders with overlapping symptoms, such as non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and cryptogenic cirrhosis.1,3

Genetic counseling and testing for mutations caused by disease are recommended for all biological siblings, regardless of signs and symptoms, in order to detect carriers.3 Physicians can request prenatal genetic testing (amniocentesis or chorionic villus sampling) in case of expectant progenitors with one or more LAL-D-confirmed children.3

Plasma lipids should be assessed and monitored in all patients with LAL-D.1,3 Most patients present with high levels of low-density lipoprotein (LDL) and low levels of high-density lipoprotein (HDL) cholesterols at diagnosis.7 In case of other cardiovascular risk factors or family history of cardiovascular disease, the assessment of very low-density lipoprotein (VLDL) cholesterol, chylomicrons and advanced lipid testing should be considered.3

For adult patients, cardiac evaluation by a cardiologist is recommended.3 Carotid intima-media thickness testing can be used to assess subclinical atherosclerotic burden in children and adults with LAL-D. Additional noninvasive optional assessments include ankle-brachial index test, angioCT, and coronary artery calcium scan.3

The first-line hepatic evaluation should include the assessment of liver enzymes, presence of microvesicular steatosis, and extent of fibrosis/cirrhosis.1,3 Examination of serum levels of alanine aminotransferase (ALT), aspartate aminotransaminase (AST), and γ-glutamyltransferase (GGT), which are indicators of liver injury, is recommended.3 Hepatic fibrosis can be assessed noninvasively by transient elastography or other imaging methods, like acoustic radiation force impulse imaging and shear-wave transient elastography.3 Transient elastography using FibroScan® is a first-line method for the detection of fibrosis and cirrhosis in non-obese patients.8 Though validation in LAL-D children is still lacking, there are some reports describing its use.9,10 Specific lysosomal markers, such as lysosomal-associated membrane protein (LAMP)1, LAMP2, and lysosomal integral membrane protein (LIMP)2 can also be detected in paraffin-embedded tissue samples upon liver biopsy.11 If available, radiological methods, such as magnetic hepatic resonance, can be used to characterize and monitor the hepatic lipid signature.12

Though there is limited knowledge about renal involvement in LAL-D, renal vascular lipid deposition has been previously reported in patients.13 Therefore, renal evaluation of kidney function biomarkers (eg, blood urea nitrogen, serum creatinine, estimated glomerular filtration rate) is recommended for all LAL-D patients.3

Anemia and thrombocytopenia are often present in LAL-D as secondary complications of splenomegaly.4,14 Thus, hematologic assessments of complete blood count and coagulation tests are also recommended.3

Intestinal biopsy should be considered in LAL-D children presenting diarrhea and growth failure.3

Ongoing Monitoring

The consensus of guideline recommendations published by Kohli and colleagues provides a schedule for the continuous monitoring of disease progression and effectiveness of therapeutic interventions.3

A comprehensive clinical evaluation is recommended every 3 months up to 1 year and annually thereafter.3

Cardiovascular evaluation and assessment of the lipid profile should also be performed every 3 months up to 1 year but then 6 to 12 months thereafter.3 Additional noninvasive cardiovascular assessments should be performed every 1 to 2 years for patients with atherosclerosis and every 2 to 5 years for stable patients.

Hepatic evaluation should be carried out at 1 month, every 3 months up to 1 year, and 6 to 12 months thereafter.3 Noninvasive liver assessment with transient elastography or other imaging methods should happen annually.

Renal evaluation is recommended for all patients every 6 to 12 months.3

Hematologic assessments are recommended annually.3

Signs of malabsorption in children should be closely monitored to prevent poor growth and developmental delays.3

Antibody testing for anti-drug antibodies should be performed if an infusion-associated reaction to enzyme replacement treatment is suspected.3

LAL-D patients should receive care and monitoring from an interdisciplinary team of healthcare specialists, but one specialist should be nominated to coordinate and ensure cohesive disease management.3 Additional special support should be considered based on individual needs.

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. Kohli R, Ratziu V, Fiel MI, Waldmann E, Wilson DP, Balwani M. Initial assessment and ongoing monitoring of lysosomal acid lipase deficiency in  children and adults: Consensus recommendations from an international collaborative working group. Mol Genet Metab. 2020;129(2):59-66. doi:10.1016/j.ymgme.2019.11.004

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. 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

6. Lukacs Z, Barr M, Hamilton J. Best practice in the measurement and interpretation of lysosomal acid lipase in  dried blood spots using the inhibitor Lalistat 2. Clin Chim Acta. 2017;471:201-205. doi:10.1016/j.cca.2017.05.027

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. Afdhal NH. Fibroscan (transient elastography) for the measurement of liver fibrosis. Gastroenterol Hepatol (N Y). 2012;8(9):605-607. https://pubmed.ncbi.nlm.nih.gov/23483859

9. de Lédinghen V, Le Bail B, Rebouissoux L, et al. Liver stiffness measurement in children using fibroscan: feasibility study and  comparison with fibrotest, aspartate transaminase to platelets ratio index, and liver biopsy. J Pediatr Gastroenterol Nutr. 2007;45(4):443-450. doi:10.1097/MPG.0b013e31812e56ff

10. Alkhouri N, Sedki E, Alisi A, et al. Combined paediatric NAFLD fibrosis index and transient elastography to predict clinically significant fibrosis in children with fatty liver disease. Liver Int  Off J Int Assoc  Study Liver. 2013;33(1):79-85. doi:10.1111/liv.12024

11. 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

12. Thelwall PE, Smith FE, Leavitt MC, et al. Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: non-invasive identification and treatment monitoring by magnetic resonance. J Hepatol. 2013;59(3):543-549. doi:https://doi.org/10.1016/j.jhep.2013.04.016

13. Kale AS, Ferry GD, Hawkins EP. End-stage renal disease in a patient with cholesteryl ester storage disease  following successful liver transplantation and cyclosporine immunosuppression. J Pediatr Gastroenterol Nutr. 1995;20(1):95-97. doi:10.1097/00005176-199501000-0001614.

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.

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