Diagnosing Lysosomal Acid Lipase Deficiency (LAL-D)

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LAL-D AND SEVERE LIVER DISEASE

Are patients with LAL-D hiding in your practice?

Liver abnormalities in LAL-D share clinical presentation with other conditions—test for LAL-D to avoid misdiagnosis.^1-7

^a At baseline, patients in a clinical trial evaluating a potential treatment for LAL-D had a mean LDL-c of 5.4 mmol/L and a mean HDL-c of 0.8 mmol/L; 73% (48/66) of patients had ALT ≥1.5x ULN and <3x ULN, and 27% (18/66) of patients had ALT ≥3x ULN. An ALT ≥1.5x ULN according to specified gender-specific normal ranges was one of the eligibility criteria for enrollment.^2,4

^bAbove age- and gender-specific ULN.³

^cIn adult patients (mmol/L): LDL-c ≥4.1 (≥3.4 in patients on LLMs).^3,4,7

^dIn adult patients (mmol/L): HDL-c ≤1.0 (males)/≤1.3 (females).^3,4,7

^e BMI ≤95th percentile for age and gender.^2,3

Abbreviations: BMI, body mass index; LLM, lipid-lowering medication; ULN, upper limit of normal.

ELEVATED LDL-C LEVELS DIFFERENTIATE LAL-D FROM NAFLD/NASH⁵

Studies on LAL-D reveal elevated LDL-c levels compared with NAFLD/NASH^2,8-13

NOTE: These studies represent individual publications using different populations of patients. Data are not directly comparable.

^aBaseline values for patients with LAL-D in a clinical study; 32% [15/47] of pediatric patients <18 years of age and 58% [11/19] of adult patients ±18 years of age were on lipid-lowering medications [LLMs].²

^b Data reported as mean and 95% Cl.⁹

^c Data reported as median; 25th to 75th percentile, 2.0 to 3.0 mmol/L.¹⁰

Narrowing The Diagnosis

Additional clinical findings can differentiate LAL-D from NAFLD or NASH^5,14

LDL-c

Elevated

Normal to elevated

ALT

Elevated

Elevated (may normalize with weight loss)

Patients with low HDL-c, normal BMI, rapidly progressive fibrosis/cirrhosis, or microvesicular or mixed steatosis may not have NAFLD/NASH^2-5,15

INCLUDE LAL-D EARLY IN YOUR LIVER DIAGNOSTIC WORKUP^3,6

When evaluating pediatric patients for liver disease by lab test or imaging, test for LAL-D prior to biopsy^3,6

ESPGHAN guidelines for liver biopsy recommend that differential diagnosis for LAL-D in children be based on blood test prior to biopsy.¹⁶

AASLD guidelines for NAFLD advise ruling out competing etiologies of hepatic steatosis, such as LAL-D, prior to biopsy.¹⁷

Pediatric NHLBI guidelines for cardiovascular health and APS guidelines for diagnosis and treatment of hyperlipidemia recommend lipid screening for children.^2,18,19

^aAge- and gender-specific³

^bIn pediatric patients⁴

^cNHLBI guildines recommend universal lipid screening for children 9-11 and 18-21 years old; APS guidelines recommend cholesterol testing for every child or adolescent, preferably before the age of 6^2,18,19

Abbreviations: AASLD, American Association for the Study of Liver Diseases; APS, Arbeitsgemeinschaft für Pädiatrische Stoffwechselstörungen; Cu, copper; ESPGHAN, European Society for Paediatric Gastroenterology Hepatology and Nutrition; Fe, iron; HBV, hepatitis B virus; HCV, hepatitis C virus; NHLBI, National Heart, Lung, and Blood Institute; TIBC, total iron-binding capacity.

LAL-D AND DYSLIPIDEMIA

Are patients with LAL-D hiding in your practice?

Lipid abnormalities in LAL-D share clinical presentation with other conditions—test for LAL-D to avoid misdiagnosis^1-7

^aAt baseline, patients in a clinical trial evaluating a potential treatment for LAL-D had a mean LDL-c of 5.4 mmol/L and a mean HDL-c of 0.8 mmol/L; 73% (48/66) of patients had ALT ≥1.5x ULN and <3x ULN, and 27% (18/66) of patients had ALT ≥3x ULN. An ALT ≥1.5x ULN according to specified gender-specific normal ranges was one of the eligibility criteria for enrollment.^2,4

^b In adult patients (mmol/L): LDL-c ≥4.1 (≥3.4 in patients on LLMs).^3,4,6

^cIn adult patients (mmol/L): HDL-c ≤1.0 (males)/≤1.3 (females).^3,4,6

^dAbove age- and gender-specific ULN.³

^eBMI ≤95th percentile for age and gender.^2,3

Abbreviations: BMI, body mass index; LLM, lipid-lowering medication; ULN, upper limit of normal.

Elevated LDL-C LEVELS DIFFERENTIATE LAL-D FROM METABOLIC SYNDROME^1,8-10

LDL-c levels reported for patients with LAL-D are higher than those reported in metabolic syndrome studies^2,11-13

NOTE: These studies represent individual publications using different populations of patients. Data are not directly comparable.

^a Baseline values for patients with LAL-D in a clinical study; 32% [15/47] of pediatric patients <18 years of age and 58% [11/19] of adult patients ±18 years of age were on lipid-lowering medications [LLMs].²

^b Metabolic syndrome was defined using previously published definitions.^12,13

^cLDL-c levels in African-American and Caucasian patients are shown in cohorts 1 and 2, respectively.¹²

^dLDL-c levels in female and male patients are shown in cohorts 1 and 2, respectively.¹³

^e Data reported as mean ±SE.¹²

NARROWING THE DIAGNOSIS

Use these clinical findings to differentiate LAL-D from metabolic syndrome^1,8-10

LDL-c

Elevated

Normal to elevated

ALT

Elevated

Normal to elevated (may normalize with weight loss)

Prevalence of metabolic syndrome increases with age; patients with normal BMI, normal fasting blood glucose, normal blood pressure, and resistance to LLMs may not have metabolic syndrome¹⁴

INCLUDE LAL-D EARLY IN YOUR DYSLIPIDEMIA WORKUP^3,5,a

When evaluating pediatric patients for secondary causes of dyslipidemia, test for LAL-D prior to genetic screening^3,5

^aLAL-D is historically known as Wolman disease or CESD³

^bDrug therapies such as corticosteroids, isotretinoin, beta-blockers, oral contraceptives, chemotherapeutic agents, aniretroviral agents¹⁶

Pediatric NHLBI guidelines for cardiovascular health recommend universal lipid screening for children 9 to 11 and and 18 to 21 years of age.⁷

Additionally, pediatric APS guidelines for diagnosis and treatment of hyperlipidemia recommend cholesterol testing for every child or adolescent.^2,17

Abbreviations: APS, Arbeitsgemeinschaft für Pädiatrische Stoffwechselstörungen; HeFH, heterozygous familial hypercholesterolemia; NHLBI, National Heart, Lung, and Blood Institute.

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References: 1. Bernstein DL, et al. J Hepatol. 2013;58:1230-43. doi:10.1016/j.jhep.2013.02.014. 2. Data on file, Alexion Pharmaceuticals. 3. Reiner Ž, et al. Atherosclerosis. 2014;235:21-30. doi:10.1016/j.atherosclerosis.2014.04.003. 4. Burton BK, et al. N Engl J Med. 2015;373:1010-20. doi:10.1056/NEJMoa1501365. 5. Burton BK, et al. J Pediatr Gastroenterol Nutr. 2015;61:619-25. doi:10.1097/MPG.0000000000000935. 6. Hamilton J, et al. Clin Chim Acta. 2012;413:1207-10. doi:10.1016/j.cca.2012.03.019. 7. Daniels SR, et al. Pediatrics. 2008;122:198-208. doi:10.1542/peds.2008-1349. 8. Xu Y-P, et al. World J Gastroenterol. 2013;19:5897-903. doi:10.3748/wjg.v19.i35.5897. 9. Pacifico L, et al. Nutr Metab Cardiovasc Dis. 2013;23:1010-6. doi:10.1016/j.numecd.2012.08.003. 10. Nobili V, et al. Pediatr Res. 2010;67:665-70. doi:10.1203/PDR.0b013e3181da4798. 11. Rhee E-J. Endocr J. 2013;60:743-52. 12. Targher G, et al. Clin Sci. 2013;125:301-9. doi:10.1042/CS20130036. 13. Foster T, et al. Dig Dis Sci. 2013;58:2392-8. doi:10.1007/s10620-013-2652-7. 14. Preiss D, et al. Clin Sci. 2008;115:141-50. doi:10.1042/CS20070402. 15. Hülkova H, et al. Histopathology. 2012;60:1107-13. doi:10.1111/j.1365-2559.2011.04164.x. 16. Dezsőfi A, et al. J Pediatr Gastroenterol Nutr. 2015;60:408-20. doi:10.1097/MPG.0000000000000632. 17. Chalasani N, et al. Gastroenterology. 2012;142:1592-609. doi:10.1053/j.gastro.2012.04.001. 18. National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/files/docs/peds_guidelines_sum.pdf. Published October 2012. Accessed August 23, 2016. 19. Chourdakis M, et al. http://www.awmf.org/uploads/tx_szleitlinien/027-068l_s2k_Hyperlipid%C3%A.... Published 2015. Accessed August 23, 2016.

References: 1. Bernstein DL, et al. J Hepatol. 2013;58:1230-43. doi:10.1016/j.jhep.2013.02.014. 2. Data on file, Alexion Pharmaceuticals. 3. Reiner Ž, et al. Atherosclerosis. 2014;235:21-30. doi:10.1016/j.atherosclerosis.2014.04.003. 4. Burton BK, et al. N Engl J Med. 2015;373:1010-20. doi:10.1056/NEJMoa1501365. 5. Hamilton J, et al. Clin Chim Acta. 2012;413:1207-10. doi:10.1016/j.cca.2012.03.019. 6. Daniels SR, et al. Pediatrics. 2008;122:198-208. doi:10.1542/peds.2008-1349. 7. Grundy SM, et al. Circulation. 2004;109:433-8. doi:10.1161/01.CIR.0000111245.75752.C6. 8. Preiss D, et al. Clin Sci. 2008;115:141-50. doi:10.1042/CS20070402. 9. Kaur J. Cardiol Res Pract. 2014;943162. doi:10.1155/2014/943162. 10. Holvoet P, et al. Diabetes. 2004;53:1068-73. 11. Burton BK, et al. J Pediatr Gastroenterol Nutr. 2015;61:619-25. doi:10.1097/MPG.0000000000000935. 12. Lee S, et al. J Pediatr. 2008;152:177-84. doi:10.1016/j.jpeds.2007.07.053. 13. Hong Y, et al. J Intern Med. 2007;262:113-23. doi:10.1111/j.1365-2796.2007.01781.x. 14. Aguilar M, et al. JAMA. 2015;313:1973-4. doi:10.1001/jama.2015.4260. 15. Abel F, et al. Poster presented at: the International Liver Congress 2016. April 13-17, 2016; Barcelona, Spain. 16. National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/files/docs/peds_guidelines_sum.pdf. Published October 2012. Accessed August 23, 2016. 17. Chourdakis M, et al. http://www.awmf.org/uploads/tx_szleitlinien/027-068l_s2k_Hyperlipid%C3%A.... Published 2015. Accessed August 23, 2016