Cholesteryl ester storage disease: Review of the findings in 135 reported patients with an underdiagnosed disease

• Published in: Journal of hepatology Vol. 58; no. 6; pp. 1230 - 1243
• Main Authors: Bernstein, Donna L, Hülkova, Helena, Bialer, Martin G, Desnick, Robert J
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2013
• Subjects: Cholesterol - blood; Cholesterol Ester Storage Disease - complications; Cholesterol Ester Storage Disease - diagnosis; Cholesterol Ester Storage Disease - genetics; Cholesterol Ester Storage Disease - pathology; Cholesterol Ester Storage Disease - therapy; Cholesteryl ester storage disease; Elevated serum transaminases; Enzyme Replacement Therapy; Gastroenterology and Hepatology; Hepatomegaly; Humans; Liver - pathology; Liver Transplantation; Lysosomal acid lipase deficiency; Lysosomal storage disease; Micronodular cirrhosis; Microvesicular steatosis; Non-alcoholic fatty liver disease (NAFLD); Non-alcoholic steatohepatitis; Triglycerides - blood; Type 2b dyslipidemia; Wolman Disease; Wolman Disease - complications; Wolman disease; exon 8 splice-junction mutation; NAFLD; non-alcoholic fatty liver disease; enzyme replacement therapy; LIMP; E8SJM; ERT; Non-alcoholic fatty liver disease (NAFLD); alanine aminotransferase; ALT; CHO; Elevated serum transaminases; WD; LIPA; Hepatomegaly; Non-alcoholic steatohepatitis; ApoB; ABCA1; lysosomal acid lipase; AST; CE; lysosomal integral membrane; Lysosomal acid lipase deficiency; HMG-CoA; Lysosomal storage disease; CESD; NASH; Cholesteryl ester storage disease; 3-hydroxy-3-methylglutaryl coenzyme A; ATP binding cassette transporter 1; recombinant human LAL; aspartate aminotransferase; Microvesicular steatosis; Micronodular cirrhosis; lysosomal associated membrane protein; lysosomal acid lipase gene; Chinese hamster ovary; LAL; rhLAL; LAMP; apolipoprotein B; cholesteryl ester; Type 2b dyslipidemia
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2013.02.014

Summary 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.