What Is Cholesteryl Ester Storage Disease?

Introduction to cholesteryl ester storage disease

Cholesteryl ester storage disease (CESD) is a condition where the body struggles to produce an enzyme called lysosomal acid lipase (LAL), causing progressive metabolic liver disease. CESD is a type of lysosomal acid lipase deficiency, meaning that the enzyme LAL is at lower than normal levels and cannot work properly.¹  

The broad term for conditions that affect enzymes of the lysosomes is lysosomal storage diseases (LSDs), which include around 50 conditions, of which CESD is a rare form.² CESD occurs in an estimated 1 in 40,000–300,000 individuals.³ 

This article will explain the symptoms, genetic factors, disease mechanisms, diagnosis, and treatments available for CESD.

Overview of lysosomes and cholesteryl ester

Lysosomes are an important component within cells that are responsible for breaking down lipids (fats) and other molecules so that their components can be reused. Lysosomes degrade components within the body that are no longer necessary.²

The lysosomal acid lipase (LAL) enzyme is important for breaking down cholesteryl esters, a storage form of cholesterol, into cholesterol that can move through the body. The LAL enzyme is found in lysosomes and is important for the normal function of lysosomes. LAL also degrades triglycerides within lysosomes.⁴

Causes of cholesteryl ester storage disease

Cholesteryl ester storage disease (CESD) is inherited in an autosomal recessive pattern, which means that a copy of the CESD gene must be inherited from both the mother and the father to present with CESD. Mutations that cause CESD are found in the lysosomal acid lipase gene, called LIPA.¹ Mutations in LIPA reduce the activity of LAL - an enzyme important for breaking down cholesterol.²

Disease mechanism

As cholesteryl ester storage disease (CESD) causes lower levels of lysosomal acid lipase (LAL) in the lysosomes, cholesteryl esters and triglycerides cannot be broken down into cholesterol and fatty acids to move through the body.⁴ Lower levels of LAL in CESD results in a build-up of cholesteryl esters in various organs including the liver, the adrenal glands, and the intestines.¹

Symptoms of cholesteryl ester storage disease

Symptoms of cholesteryl ester storage disease (CESD) can begin during childhood or adulthood. Common symptoms include:^1,​​2

• Diarrhoea
• Vomiting
• Swollen abdomen
• Adrenal calcification in rare cases (build-up of calcium in the adrenal glands)

• Enlargement of the liver (hepatomegaly)
• Enlargement of the spleen (splenomegaly)

Symptoms of CESD vary with different levels of severity, which can mean some individuals receive a diagnosis much later in life.^1,2 People with CESD generally live into adulthood.²

Clinical features of CESD include:²

• Elevated serum transaminases, indicating liver dysfunction: aspartate transaminase (AST) and alanine transaminase (ALT)
• Elevated low-density lipoprotein (LDL) cholesterol
• Elevated triglyceride levels
• Elevated total cholesterol in the blood
• Lower levels of high-density lipoprotein (HDL) cholesterol

Diagnosis of cholesteryl ester storage disease

Enzyme assays

Tests for lysosomal acid lipase (LAL) enzyme activity in a laboratory usually find a range of activity from 1% to 12% of the normal activity. This means that the LAL enzyme is working less effectively than it would under normal conditions.¹ LAL enzyme levels can be tested by taking a sample from a tissue in the body and performing an enzyme activity assay. This type of test is also done by testing a sample from the amniotic fluid during pregnancy if there is a known genetic family history of CESD.²

Genetic testing 

Genetic testing for the presence of mutations in the LIPA gene helps diagnose CESD. Sequencing can help to confirm the cause of elevated LAL levels from enzyme assays.²

Liver biopsy

A liver biopsy is used to determine the cause of liver damage, as other conditions also cause damage to the liver. A liver biopsy combined with tests for lysosomal markers is necessary to determine if the individual has CESD. This is effective in detecting the difference between non-alcoholic fatty liver disease and CESD as the cause of liver damage and cirrhosis (scarring).²

Overlap of symptoms with related conditions

A type of lysosomal acid lipase (LAL) deficiency that is more severe than CESD is Wolman disease, which occurs in infancy and can lead to death within the first year of life due to liver failure, malnutrition, and poor absorption of nutrients.² Wolman disease has similar symptoms to the less severe CESD.¹ However, people with Wolman disease more commonly have calcification in the adrenal glands and have levels of LAL that are considered non-functioning (less than 1% of the normal activity).²

Other frequent misdiagnoses of CESD include conditions of the liver. This usually occurs when a liver biopsy is taken, which can show similar characteristics to non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and cirrhosis of unknown causes.^1,4

Complications

Over time, CESD leads to liver damage combined with cirrhosis and liver failure due to the build-up of lipids in the liver.² CESD also contributes to atherosclerosis and heart disease due to the build-up of cholesterol and fatty acids in the arteries. There is an increased risk of stroke and aneurysm in people with CESD.⁴

Management and treatment

Management and monitoring

It is important to monitor the progression of disease in CESD to adjust treatment and determine the level of complications in organs. Conducting liver function tests every year for levels of AST, ALT, and other markers of liver damage is recommended. Blood tests to test for inflammatory markers and find abnormal lipid levels are important. Monitoring of the level of enlargement of the liver and spleen can be done using MRI scans. Liver transplants are necessary in some cases where liver damage is severe. Due to complications that can occur in the heart, a regular electrocardiogram (ECG) is also recommended.¹

Treatment 

Enzyme replacement therapy

Enzyme replacement therapy is the primary treatment for people with CESD. It involves giving the enzyme LAL through a vein to replenish levels of LAL, which are low in people with CESD. When levels of LAL increase in the body, the built-up cholesteryl ester and other lipids can be broken down, thereby improving symptoms.²

Statins

A group of drugs called statins have been used to treat CESD. Statins work by reducing cholesterol levels, which can improve symptoms of CESD as less cholesterol builds up in organs such as the liver.² 

Summary

Cholesteryl ester storage disease (CESD) is a rare inherited condition resulting in the accumulation of cholesteryl esters in the body. It is caused by mutations in the LIPA gene, resulting in deficient lysosomal acid lipase (LAL) enzyme production in the lysosomes. Therefore, cholesteryl ester and triglycerides cannot be broken down into cholesterol. This leads to the build-up of cholesteryl esters and triglycerides in the liver, spleen, and intestines. 

CESD symptoms include diarrhoea, vomiting, and enlargement of the liver and spleen, and can begin during childhood or adulthood. Diagnosis involves enzyme assays, genetic testing, and liver biopsy. Untreated CESD can lead to complications including liver damage, atherosclerosis, and heart disease. Treatment options include enzyme replacement therapy and statins, along with regular monitoring of organ function. 

It is important to seek medical advice from your healthcare professional if you feel like you display symptoms.

FAQs

What is cholesteryl ester storage disease?

Cholesteryl ester storage disease (CESD) is a rare genetic disorder where cholesteryl ester, a storage form of cholesterol, is not broken down. This leads to the accumulation of cholesteryl ester in various tissues, primarily the liver and spleen, causing a range of symptoms such as hepatomegaly (enlarged liver), splenomegaly (enlarged spleen), and potential liver and cardiovascular complications.

What is the difference between cholesteryl ester and cholesterol?

Cholesteryl ester is a compound formed when a cholesterol molecule binds with a fatty acid, creating a stable storage form of cholesterol. Cholesterol itself is a type of lipid molecule that plays vital roles in cell membrane structure, hormone production, and other processes in the body. Cholesteryl ester is a way for the body to store excess cholesterol for later use. Cholesteryl ester needs to be properly broken down to maintain balanced cholesterol levels.

What is the difference between cholesteryl ester storage disease and Wolman disease?

Both cholesteryl ester storage disease (CESD) and Wolman disease are rare genetic disorders involving lipid metabolism. They differ in their causes and onset of disease. CESD can begin in infancy, childhood, or adulthood while Wolman disease occurs in infancy. CESD usually causes less severe symptoms than Wolman disease. However, the symptoms are very similar and include enlargement of the liver (hepatomegaly), enlargement of the spleen (splenomegaly), vomiting, diarrhoea, swollen abdomen, and adrenal calcification.