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.