Cholesteryl ester storage disease
|Cholesteryl ester storage disease (CESD)|
|Classification and external resources|
Cholesteryl ester storage disease (CESD) is the late onset phenotype for lysosomal acid lipase deficiency, a Lysosomal storage disease, which also has an early onset phenotype known as Wolman disease that primarily affects infants. CESD can present in childhood but often goes unrecognized until adulthood when the underlying pathology is advanced. Many of the signs and symptoms are common to patients with other liver conditions.
CESD is an autosomal recessive genetic condition and is characterized by hepatomegaly, persistently abnormal LFTs and type II hyperlipidemia. Splenomegaly and evidence of mild hypersplenism may affect some patients. Untreated, CESD may lead to fibrosis, cirrhosis, liver failure and death.
Disease Risk In Families:
• 25 per million incidence
• Autosomal recessive disorder, LAL deficiency is carried on chromosome 10
• Parents with an affected son or daughter have a 1 in 4 chance of having another affected child
Diagnosis and testing
Patients with cholesteryl ester storage disease typically have elevated cholesterol and triglyceride levels (type II hyperlipidemia) and may present at an early age with the following liver abnormalities:
• Unexplained hepatomegaly
• Elevated transaminases
• Unexplained fatty liver
• Progressive and/or unexplained chronic liver disease
Type II hyperlipidemia in association with unexplained fatty liver or elevated transaminases in more than one sibling in a family would warrant consideration of a diagnosis of CESD.
Patients with CESD are typically investigated for infectious, metabolic and autoimmune liver disease. Imaging may suggest hepatic steatosis and liver biopsies when performed show accumulation of fat in hepatocytes and Kupffer cells. Periportal fibrosis and cirrhosis is not uncommon. Descriptive terms including sea blue Histiocytosis may be applied to the liver abnormalities.
Useful diagnostic clues
• Low normal High-density lipoprotein (HDL)(<10th percentile or <35 mg/dL for men and women), especially very low HDL (<5–10 mg/dL)
• Excessive hepatomegaly and/or transaminase increase for a given BMI
• Unusual coexisting lymphadenopathy or enlarged lymph nodes
• Onset of liver abnormalities in childhood
• Clinical suspicion of visceral Niemann Pick not confirmed by enzyme analysis
• An enlarged spleen that is disproportionate in size to the degree of liver involvement/disease
Challenges in diagnosis
Cholesteryl ester storage disease (CESD) is rare and can be difficult to diagnose. Recent studies using genetic analysis suggest that heterozygote carriers of a common disease causing mutation for CESD are more common than previously thought with a carrier frequency for this mutation of about 1 in 200 or 5000 per million. Based on these carrier frequencies and the mutation spectrum of published CESD cases this translates to an estimate of approximately 25 cases of CESD per million births.
Delayed diagnosis may be the result of disease under-recognition and/or symptoms being mistaken for those of other disorders, such as:
Clinical diagnosis is based upon presentation of signs, symptoms and laboratory abnormalities (lipids, liver transaminases) and may be confirmed by enzyme assay (blood test) detecting low or absent levels of lysosomal acid lipase or in relatives of affected patients by mutation linkage analysis (blood test).
There is no disease modifying treatment for cholesteryl ester storage disease (CESD). Combining drugs that reduce blood cholesterol with a low cholesterol diet has been effective at reducing some of the symptoms associated with this genetic disorder.
Synageva BioPharma Corp. of Lexington, Massachusetts, is recruiting patients to participate in a clinical trial that evaluates an enzyme replacement therapy of lysosomal acid lipase (LAL) deficiency. For more information, refer to the Synageva.com.
- Sandro Muntoni, Heiko Wiebusch, Marianne Jansen-Rust, Stephan Rust, Udo Seedorf, et al.; "Prevalence of Cholesteryl Ester Storage Disease." Journal of the American Heart Association, Arterioscler. Thromb. Vasc. Biol., 2007; 27; 1866-1868
- Peter J. Meikle; John J. Hopwood; Alan E. Clague; et al. "Prevalence of Lysosomal Storage Disorders." JAMA, 1999; 281(3): 249-254
- Synageva BioPharma Corp.
- Clinical Trials.gov
- Hide and Seek Foundation For Lysosomal Disease Research
- Lipid Storage Diseases Fact Sheet at ninds.nih.gov
- LAL Solace (Support Organization for LAL Deficiency - Advocacy, Care and Expertise)