Clinical Features of Lysosomal Acid Lipase Deficiency

Barbara K Burton, Patrick B Deegan, Gregory M Enns, Ornella Guardamagna, Simon Horslen, Gerard K Hovingh, Steve J Lobritto, Vera Malinova, Valerie A McLin, Julian Raiman, Maja Di Rocco, Saikat Santra, Reena Sharma, Jolanta Sykut-Cegielska, Chester B Whitley, Stephen Eckert, Vassili Valayannopoulos, Anthony G Quinn, Barbara K Burton, Patrick B Deegan, Gregory M Enns, Ornella Guardamagna, Simon Horslen, Gerard K Hovingh, Steve J Lobritto, Vera Malinova, Valerie A McLin, Julian Raiman, Maja Di Rocco, Saikat Santra, Reena Sharma, Jolanta Sykut-Cegielska, Chester B Whitley, Stephen Eckert, Vassili Valayannopoulos, Anthony G Quinn

Abstract

Objective: The aim of this study was to characterize key clinical manifestations of lysosomal acid lipase deficiency (LAL D) in children and adults.

Methods: Investigators reviewed medical records of LAL D patients ages ≥5 years, extracted historical data, and obtained prospective laboratory and imaging data on living patients to develop a longitudinal dataset.

Results: A total of 49 patients were enrolled; 48 had confirmed LAL D. Mean age at first disease-related abnormality was 9.0 years (range 0-42); mean age at diagnosis was 15.2 years (range 1-46). Twenty-nine (60%) were male patients, and 27 (56%) were <20 years of age at the time of consent/assent. Serum transaminases were elevated in most patients with 458 of 499 (92%) of alanine aminotransferase values and 265 of 448 (59%) of aspartate aminotransferase values above the upper limit of normal. Most patients had elevated low-density lipoprotein (64% patients) and total cholesterol (63%) at baseline despite most being on lipid-lowering therapies, and 44% had high-density lipoprotein levels below the lower limit of normal. More than half of the patients with liver biopsies (n = 31, mean age 13 years) had documented evidence of steatosis (87%) and/or fibrosis (52%). Imaging assessments revealed that the median liver volume was ∼1.15 multiples of normal (MN) and median spleen volume was ∼2.2 MN. Six (13%) patients had undergone a liver transplant (ages 9-43.5 years).

Conclusion: This study provides the largest longitudinal case review of patients with LAL D and confirms that LAL D is predominantly a pediatric disease causing early and progressive hepatic dysfunction associated with dyslipidemia that often leads to liver failure and transplantation.

Trial registration: ClinicalTrials.gov NCT01528917.

Figures

FIGURE 1
FIGURE 1
Values, by patient, for (A) ALT, and (B) LDL-C. ALT = alanine aminotransferase; LDL-C = low-density lipoprotein-cholesterol.

References

    1. Grabowski GA, Du H. Lysosomal acid lipase deficiencies: the Wolman disease/cholesteryl ester storage disease spectrum. In: Valle D, Beaudet AL, Vogelstein B, et al. eds. The Online Metabolic and Molecular Basis of Inherited Metabolic Disease. New York: McGraw-Hill; 2013.
    1. Bernstein DL, Hülkova H, Bialer MG, et al. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol 2013; 58:1230–1243.
    1. Marshall WC, Ockenden BG, Fosbrooke AS, et al. Wolman's disease. A rare lipidosis with adrenal calcification. Arch Dis Child 1969; 44:331–341.
    1. Konno T, Fujii M, Watanuki T, et al. Wolman's disease: the first case in Japan. Tohoku J Exp Med 1966; 90:375–389.
    1. Krivit W, Freese D, Chan KW, et al. Wolman's disease: a review of treatment with bone marrow transplantation and considerations for the future. Bone Marrow Transplant 1992; 10 suppl 1:97–101.
    1. Jones SA, Bernstein D, Bialer M, et al. Severe and rapid disease course in the natural history of infants with lysosomal acid lipase deficiency. Mol Genet Metab 2014; 111:S57–S58.
    1. Beaudet A, Ferry GD, Nichols BL, et al. Cholesterol ester storage disease: clinical, biochemical, and pathological studies. J Pediatr 1977; 90:910–914.
    1. Gasche C, Aslanidis C, Kain R, et al. A novel variant of lysosomal acid lipase in cholesteryl ester storage disease associated with mild phenotype and improvement on lovastatin. J Hepatol 1997; 27:744–750.
    1. Muntoni S, Wiebusch H, Jansen-Rust M, et al. Prevalence of cholesteryl ester storage disease. Arterioscler Thromb Vasc Biol 2007; 27:1866–1868.
    1. Scott SA, Liu B, Nazarenko I, et al. Frequency of the cholesteryl ester storage disease common LIPA E8SJM mutation (c.894G>A) in various racial and ethnic groups. Hepatology 2013; 58:958–965.
    1. 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; 33:2909–2914.
    1. Zarrilli F, Elce A, Scorza M, et al. An update on laboratory diagnosis of liver inherited diseases. Biomed Res Int 2013; 2013:697940.
    1. Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 2009; 58:1538–1544.
    1. US Census Bureau. Statistical abstract of the United States: 2012. Accessed October 6, 2014.
    1. 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 2013; 33:79–85.
    1. Angulo P, Keach JC, Batts KP, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999; 30:1356–1362.
    1. Goodman ZD, Makhlouf HR, Liu L, et al. Pathology of chronic hepatitis C in children: liver biopsy findings in the Peds-C Trial. Hepatology 2008; 47:836–843.
    1. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115:209–218.
    1. Reeder SB, Cruite I, Hamilton G, et al. Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy. J Magn Reson Imaging 2011; 34:729–749.
    1. 2014; Valayannopoulos V, Malinova V, Honzík T, et al. Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with. 61:1135–1142.
    1. 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; 59:543–549.
    1. Elleder M, Chlumska A, Hyanek J, et al. Subclinical course of cholesteryl ester storage disease in an adult with hypercholesterolemia, accelerated atherosclerosis, and liver cancer. J Hepatol 2000; 32:528–534.
    1. Ambler GK, Hoare M, Brais R, et al. Orthotopic liver transplantation in an adult with cholesterol ester storage disease. JIMD Rep 2013; 8:41–46.
    1. Ouimet M, Marcel YL. Regulation of lipid droplet cholesterol efflux from macrophage foam cells. Arterioscler Thromb Vasc Biol 2012; 32:575–581.
    1. Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 2009; 50 suppl:S172–S177.
    1. Cholesterol Treatment Trialists’ Collaborators, Mihaylova B, Emberson J et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380:581–90.
    1. Patton HM, Yates K, Unalp-Arida A, et al. Association between metabolic syndrome and liver histology among children with nonalcoholic fatty liver disease. Am J Gastroenterol 2010; 105:2093–2102.
    1. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362:1675–1685.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa