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.

Molecular diagnosis of glycogen storage disease and disorders with overlapping clinical symptoms by massive parallel sequencing

“…Patient P20 was a carrier of two described mutations in LIPA (the gene coding for lysosomal acid lipase (LAL) MIM 613497): c.894G>A and c.398delC. 10,11 The first affects the splicing process and is frequently associated with cholesteryl ester storage disease, a mild form of LAL deficiency; the second is associated with a much more severe form known as Wolman disease. The defect was confirmed by enzyme assay in dried blood samples that showed significantly reduced LAL activity (enzyme activity <0.02 nmol/punch/hour; reference range: 0.37-2.30 nmol/ punch/hour).…”

Lysosomal Acid Lipase Deficiency Unmasked in Two Children With Nonalcoholic Fatty Liver Disease

“…In spite of the later presentation in these patients, there is evidence of clinically significant liver disease and liver-related mortality among children and adolescents with LAL-D, underscoring the importance of identifying affected patients. 3 The diagnosis of LAL-D, particularly in children and adolescents, is hampered by the lack of specific clinical findings, the broad spectrum of disease presentation, and significant overlap with more common diseases. In primary care practices, as well as specialty clinics, features of LAL-D, like hepatic steatosis, elevated aminotransferases, and dyslipidemia, are more often seen coexisting with conditions like nonalcoholic fatty liver disease (NAFLD), metabolic syndrome, abstract Lysosomal acid lipase deficiency (LAL-D) is a classic lysosomal storage disorder characterized by accumulation of cholesteryl ester and triglyceride.…”

Liver disease and dyslipidemia as a manifestation of lysosomal acid lipase deficiency (LAL-D). Clinical and diagnostic aspects, and a new treatment. An update

“…8 Developmental delay and/or irritability are secondary to malnutrition, overall compromise, and hospitalization resulting from the central nervous system involvement caused by this disease. 9 The natural course of this clinical form results in death in the first year of life. [10][11][12] The subtype of LAL-D that starts during childhood, adolescence, or adulthood implies 1 -1 2 % o f n o r m a l e n z y m e a c t i v i t y ; l i p i d accumulation leads to progressive liver damage, elevated transaminases, steatosis, fibrosis and/ or cirrhosis.…”