Key Points
Disease summary:
Cholesteryl ester storage disease (CESD) is a lysosomal storage disorder (LSD) caused by a deficiency of lysosomal acid lipase (LAL), an enzyme necessary for the breakdown of cholesteryl esters and triglycerides.
CESD is part of the LAL deficiency spectrum. In general, mutations that allow for residual LAL enzyme function result in CESD, while Wolman disease (WD), the infantile fatal form of LAL deficiency, stems from null mutations with no residual enzyme function.
Features of CESD are predominantly a consequence of the intracellular accumulation of cholesteryl esters and triglycerides in liver, spleen, lymph nodes, and other tissues. Biopsy can show sea-blue histiocytes, large Kupffer cells with increased vacuoles, lipid droplets, or cholesterol crystals.
Individuals with CESD commonly present with an abnormal lipid profile, which can include increased total cholesterol, high low-density lipoprotein (LDL), low high-density lipoprotein (HDL), and high-normal to high triglycerides; liver and/or spleen enlargement; or other types of liver disease such as steatosis, fibrosis, or cirrhosis.
Individuals with CESD are at risk for premature atherosclerosis, liver disease, bleeding complications, and intestinal malabsorption.
Hereditary basis:
CESD is an autosomal recessive disorder caused by mutations in LIPA.
Variability can be seen in the severity of phenotypes even within families, though both CESD and WD would not be expected within the same sibship.
Differential diagnosis:
There is overlap in the clinical features of CESD and other LSDs, such as Gaucher disease (GD) and Niemann-Pick disease (NPD). Individuals with NPD may have a similar lipid profile to individuals with CESD, and hepatosplenomegaly is a common feature of all three diseases. Individuals with CESD would not be expected to have the bone disease common to GD or the lung disease common to NPD. Biochemical analysis can distinguish between LSDs.
Hyperlipidemia can be caused by both genetic and environmental factors. It is important to distinguish between CESD and other genetic causes of hyperlipidemia, such as familial hypercholesterolemia (FH). The lipid profile of FH can include high total cholesterol and LDL levels, with low HDL and normal or high triglyceride levels. FH is inherited in an autosomal dominant manner. It is essential to consider the lipid profile, the inheritance pattern, and the nonlipid associated phenotype when distinguishing between potential genetic etiologies of hyperlipidemia.
Hepatomegaly and splenomegaly are common features of other storage disorders, such as other LSDs and glycogen storage disorders (GSD). CESD can be distinguished from other storage disorders based on associated features and biochemical analysis.
Liver disease in CESD can be misdiagnosed as nonalcoholic fatty liver disease or cryptogenic cirrhosis. In the absence of an identifiable cause of liver disease, CESD should be considered.
A high index of suspicion for CESD can potentially lead to a specific diagnosis in cases of “idiopathic” liver disease.
Diagnostic Criteria and Clinical Characteristics
Deficient LAL activity is diagnostic and can be demonstrated by enzyme assay performed on peripheral blood or fibroblast sample.
(see Table 94-1) Hepatomegaly or splenomegaly is commonly a presenting feature and may be present since childhood or adolescence. It is not uncommon for diagnosis to be delayed for years after organomegaly is noted. Some individuals initially present with a catastrophic event such as a variceal bleed, stroke, or myocardial infarct.
| System | Manifestation | Wolman (W), CESD (C), or Both (B) |
|---|---|---|
| GI | Hepatocellular dysfunction with elevated enzymes | B |
| Hepatosplenomegaly (HSM) | B | |
| Hepatic steatosis, fibrosis, or cirrhosis | B | |
| Mesenteric lipodystrophy | B | |
| Malabsorption | B | |
| Diarrhea | B | |
| Esophageal varicosities | C | |
| Cardiovascular | Atherosclerosis | C |
| Pulmonary | Pulmonary hypertension | C |
| Hematologic | Anemia | B |
| Thrombocytopenia | B | |
| Endocrine | Punctate adrenal calcification, adrenal failure | B |
| Dermatologic | Xanthomas | C |
Cardiovascular disease is common due to premature atherosclerosis caused by increased LDL cholesterol (see Table 94-2), placing affected individuals at increased risk for severe complications such as stroke.
Liver disease due to increased lipid deposition is common. Manifestations can include hepatomegaly, cirrhosis, fibrosis, nonalcoholic fatty liver disease, and altered liver function with or without jaundice. Biopsy shows signs of CESD, which can include sea-blue histiocytes, large Kupffer cells with increased vacuoles, lipid droplets, or cholesterol crystals.
Splenomegaly with resultant hypersplenism and associated cytopenias including anemia and thrombocytopenia can occur.
Intestinal malabsorption due to lipid deposition in the wall of the intestinal tract can lead to diarrhea, weight loss, and associated nutritional deficits.
Varicosities
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