Summary
Cholesteryl ester storage disease (CESD) is the term used to group together deficiencies in lysosomal acid lipase associated with a less severe clinical phenotype than that seen in Wolman disease (see this term). Given the essential role played by acid lipase in endosomal and lysosomal hydrolysis of lipoproteins, the principle organs most affected by the deficiency are those in which the endocytosis of LDL is particularly vital, explaining the hepatic manifestations of the disease. In CESD, the anomalies of lipid storage mainly involve accumulation of esterified cholesterol, with anomalies in triglyceride storage being much less pronounced than in Wolman disease. The age of onset and progression of CESD are very heterogeneous with a continuous spectrum of disease between early-onset and severe forms and those that are quasi-asymptomatic, which may reflect variations in the levels of residual acid lipase activity in vivo (in vitro measurements are always very low). Although only around 50 cases have been reported in the literature, the disease is probably more frequent but less severe forms may be underdiagnosed. Hepatomegaly is the principle, and sometimes only, clinical sign. The age of onset is variable but is usually early (generally before 10-12 years of age), although onset during adulthood has been reported. In one third of cases, splenomegaly is also present. The hepatic disease may remain asymptomatic for a long period but there is a tendency for progression towards chronic insufficiency and fibrosis. Some patients have oesophageal varices or jaundice. Gastrointestinal problems (vomiting, diarrhoea) have also been reported. CESD is considered as a relatively benign condition; however, in rare cases the disease may progress towards liver failure, either directly or after cirrhosis. In such cases, a liver transplant should be considered and appears to be an effective treatment. In the majority of patients, the plasma profile reveals hyperlipidaemia. Hypercholesterolaemia is also present and is associated with an increase in LDL cholesterol levels and a decrease in HDL cholesterol, and often with various degrees of hypertriglyceridaemia. Adult patients are at significant risk of atherosclerosis. Adrenal calcification (a nearly constant feature of Wolman disease) may be detected by radiography, but is much less common in CESD. Myelograms generally reveal the presence of nonspecific foamy and/or blue histiocytes. The liver has an orange-yellow appearance and this discolouration may orientate the diagnosis if the laparotomy was indicated for another cause. The disease is transmitted as an autosomal recessive trait. The enzyme deficiency results from mutations in the acid lipase gene (LIPA or LAL), localised to 10q24-q25. Mutations leading to CESD often have less of an impact on the acid lipase protein than those observed in Wolman disease. The diagnosis is confirmed by demonstration of acid lipase deficiency, usually by testing in leukocytes or fibroblasts. Genetic analysis can also be used to confirm the diagnosis. Symptomatic treatments revolve around following a low cholesterol diet with administration of HMG-CoA reductase inhibitors (lovastatin and its derivatives), which lead to a significant decrease in the levels of plasma cholesterol, triglycerides and LDL cholesterol. Coadministration with cholestyramine, or more recently, ezetimibe has been tested with good results. At present, there is no specific treatment but encouraging results have been obtained with enzyme substitution therapy and gene therapy in mice with inactivation of the LAL gene and presenting a phenotype similar to that seen in CESD. *Author: Dr M-T. Vanier (January 2007)*.
