title: Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease.
abstract: Cholesteryl ester storage disease (CESD) is caused by deficient lysosomal acid lipase (LAL) activity, predominantly resulting in cholesteryl ester (CE) accumulation, particularly in the liver, spleen, and macrophages throughout the body. The disease is characterized by microvesicular steatosis leading to liver failure, accelerated atherosclerosis and premature demise. Although CESD is rare, it is likely that many patients are unrecognized or misdiagnosed. Here, the findings in 135 CESD patients described in the literature are reviewed. Diagnoses were based on liver biopsies, LAL deficiency and/or LAL gene (LIPA) mutations. Hepatomegaly was present in 99.3% of patients; 74% also had splenomegaly. When reported, most patients had elevated serum total cholesterol, LDL-cholesterol, triglycerides, and transaminases (AST, ALT, or both), while HDL-cholesterol was decreased. All 112 liver biopsied patients had the characteristic pathology, which is progressive, and includes microvesicular steatosis, which leads to fibrosis, micronodular cirrhosis, and ultimately to liver failure. Pathognomonic birefringent CE crystals or their remnant clefts were observed in hepatic cells. Extrahepatic manifestations included portal hypertension, esophageal varices, and accelerated atherosclerosis. Liver failure in 17 reported patients resulted in liver transplantation and/or death. Genotyping identified 31 LIPA mutations in 55 patients; 61% of mutations were the common exon 8 splice-junction mutation (E8SJM(-1G>A)), for which 18 patients were homozygous. Genotype/phenotype correlations were limited; however, E8SJM(-1G>A) homozygotes typically had early-onset, slowly progressive disease. Supportive treatment included cholestyramine, statins, and, ultimately, liver transplantation. Recombinant LAL replacement was shown to be effective in animal models, and recently, a phase I/II clinical trial demonstrated its safety and indicated its potential metabolic efficacy.
authors.affiliation: Division of Medical Genetics, North Shore-Long Island Jewish Health System, 1554 Northern Boulevard, Suite 204, Manhasset, NY 11030, United States.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Bernstein
authors.forename: Helena
authors.initials: H
authors.lastname: Hülkova
authors.forename: Martin G
authors.initials: MG
authors.lastname: Bialer
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D002784:Cholesterol / Q000097:blood; D015217:Cholesterol Ester Storage Disease / Q000150:complications / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D056947:Enzyme Replacement Therapy; D006801:Humans; D008099:Liver / Q000473:pathology; D016031:Liver Transplantation; D014280:Triglycerides / Q000097:blood; D015223:Wolman Disease / Q000150:complications
chemical_list: D014280:Triglycerides; D002784:Cholesterol