title: Lysosomal acid lipase deficiency--an under-recognized cause of dyslipidaemia and liver dysfunction.
abstract: Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. The age at onset and rate of progression vary greatly and this may relate to the nature of the underlying mutations. Patients presenting in infancy have the most rapidly progressive disease, developing signs and symptoms in the first weeks of life and rarely surviving beyond 6 months of age. Children and adults typically present with some combination of dyslipidaemia, hepatomegaly, elevated transaminases, and microvesicular hepatosteatosis on biopsy. Liver damage with progression to fibrosis, cirrhosis and liver failure occurs in a large proportion of patients. Elevated low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels are common features, and cardiovascular disease may manifest as early as childhood. Given that these clinical manifestations are shared with other cardiovascular, liver and metabolic diseases, it is not surprising that LAL-D is under-recognized in clinical practice. This article provides practical guidance to lipidologists, endocrinologists, cardiologists and hepatologists on how to recognize individuals with this life-limiting disease. A diagnostic algorithm is proposed with a view to achieving definitive diagnosis using a recently developed blood test for lysosomal acid lipase. Finally, current management options are reviewed in light of the ongoing development of enzyme replacement therapy with sebelipase alfa (Synageva BioPharma Corp., Lexington, MA, USA), a recombinant human lysosomal acid lipase enzyme.
authors.affiliation: University Hospital Center, School of Medicine, University of Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia. Electronic address: zreiner@kbc-zagreb.hr.
authors.forename: Željko
authors.initials: Ž
authors.lastname: Reiner
authors.affiliation: Department of Public and Health Sciences, Medical School, University of Turin, Piazza Polonia 94, I-10126 Turin, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Guardamagna
authors.affiliation: Department of Clinical Biochemistry, Royal Free Hospital NHS Foundation Trust, Pond Street, London NW3 2QG, UK.
authors.forename: Devaki
authors.initials: D
authors.lastname: Nair
authors.affiliation: Cardiovascular Trials Unit, Central Manchester University Hospitals NHS Foundation Trust, Oxford Road, Manchester M13 9WL, UK.
authors.forename: Handrean
authors.initials: H
authors.lastname: Soran
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, Netherlands.
authors.forename: Kees
authors.initials: K
authors.lastname: Hovingh
authors.affiliation: Department of Internal Medicine, University of Genoa, Viale Benedetto XV n. 6, 16132 Genoa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertolini
authors.affiliation: Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, St. Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Jones
authors.affiliation: University Hospital Center, School of Medicine, University of Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia.
authors.forename: Marijana
authors.initials: M
authors.lastname: Ćorić
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via Campi 287, I-41125 Modena, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
authors.affiliation: Biochemistry Department, Yorkhill Hospital, Glasgow, G3 8SJ, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hamilton
authors.affiliation: Synageva BioPharma Corp., 33 Hayden Ave., Lexington, MA 02421, USA.
authors.forename: Terence
authors.initials: T
authors.lastname: Eagleton
authors.affiliation: Lipid Clinic, Endocrinology & Nutrition Service, Institut d'Investigations Biomèdiques August Pi Sunyer, Hospital Clínic, C. Villarroel, 170, 08036 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carloss III (ISCIII), Spain. Electronic address: eros@clinic.ub.es.
authors.forename: Emilio
authors.initials: E
authors.lastname: Ros
mesh_terms: D000465:Algorithms; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D050171:Dyslipidemias / Q000175:diagnosis / Q000209:etiology*; D057487:Enzyme Therapy; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008107:Liver Diseases / Q000175:diagnosis / Q000209:etiology*; D016031:Liver Transplantation; D008297:Male; D011379:Prognosis; D015223:Wolman Disease / Q000150:complications / Q000175:diagnosis*; D004798:Enzymes
chemical_list: D004798:Enzymes
keywords: Cholesteryl ester storage disease; Dyslipidaemia; Hepatomegaly; Lysosomal acid lipase deficiency; Wolman disease