cholesterol ester storage disease

Cholesteryl Ester Storage Disease (CESD): A Rare Metabolic Disorder

Cholesteryl ester storage disease (CESD) is a rare, inherited metabolic disorder that affects the body's ability to break down and utilize cholesterol. This condition is characterized by the accumulation of cholesteryl esters and triglycerides in various tissues and organs, leading to cellular damage and organ dysfunction.

Key Features:

• Autosomal Recessive Inheritance: CESD is inherited in an autosomal recessive manner, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop the condition.
• Lysosomal Acid Lipase Deficiency: The disease is caused by a deficiency of lysosomal acid lipase (LAL), an enzyme responsible for breaking down cholesterol and triglycerides in cells.
• Cholesteryl Ester Accumulation: As a result of LAL deficiency, cholesteryl esters accumulate in various tissues and organs, including the liver, spleen, lymph nodes, and blood vessels.
• Organ Dysfunction: The accumulation of cholesteryl esters leads to cellular damage and organ dysfunction, particularly affecting the liver, heart, and blood vessels.

Symptoms:

• Liver Enlargement: CESD can cause an enlarged liver (hepatomegaly) due to the accumulation of cholesteryl esters.
• High Blood Fats: The condition is characterized by high levels of cholesterol and triglycerides in the blood.
• Cardiovascular Disease: CESD increases the risk for cardiovascular disease, including atherosclerosis, heart attack, and stroke.
• Gastrointestinal Symptoms: Some individuals may experience gastrointestinal symptoms, such as diarrhea and weight loss.

References:

• [1] Cholesteryl ester storage disease and Wolman disease are hereditary metabolic disorders called lipid storage diseases (lipidoses).They are caused by a buildup of types of cholesterol and triglycerides in the tissues. These diseases cause high levels of fats in the blood and an enlarged liver.
• [3] Sep 14, 2023 — Cholesteryl Ester Storage Disease (CESD) is a rare autosomal recessive multisystem condition that belongs to the lysosomal storage disorders family.
• [12] People with Cholesteryl ester storage disease may also build up fatty deposits on the artery walls (atherosclerosis). This buildup can narrow the arteries and increase the risk for heart attack or stroke.

Symptoms of Cholesterol Ester Storage Disease

Cholesterol ester storage disease (CESD) can manifest itself at any age, from childhood to adulthood. The clinical symptoms are severe in babies and milder in adults.

• Gastrointestinal symptoms: Patients with CESD may experience gastrointestinal symptoms including diarrhea, abdominal pain, and malabsorption [3]. Individuals with CESD often have poor absorption of nutrients leading to malnutrition and poor growth [4].
• Abdominal pain and bleeding: Abdominal pain is common and is often accompanied by growth failure and chronic diarrhea. Hepatomegaly, splenomegaly, and malabsorption are usual [5].
• Hepatosplenomegaly and jaundice: The clinical presentation includes hepatosplenomegaly, jaundice, diarrhea, vomiting followed by severe malabsorptive malnutrition, failure to thrive, and death [8].
• Malabsorptive malnutrition: Patients with CESD often experience malabsorption of nutrients leading to malnutrition and poor growth [4].
• Decreased HDL cholesterol and increased triglycerides: Symptoms include decreased HDL cholesterol and increased triglycerides [7].

Other symptoms

• Hepatomegaly and hyperlipidemia: The most common presorted symptoms of the disease are hepatomegaly and hyperlipidemia [9].
• Excessive sweating: Some patients may experience excessive sweating, particularly in the hands and fingers [10].
• Atherosclerosis: People with CESD may also build up fatty deposits on the artery walls (atherosclerosis), which can narrow the arteries and increase the risk for heart attack or stroke [12].

References

[3] - Gastrointestinal symptoms including diarrhea, abdominal pain, and malabsorption. [4] - Poor absorption of nutrients leading to malnutrition and poor growth. [5] - Abdominal pain is common and is often accompanied by growth failure and chronic diarrhea. [7] - Decreased HDL cholesterol and increased triglycerides. [8] - Hepatosplenomegaly, jaundice, diarrhea, vomiting followed by severe malabsorptive malnutrition, failure to thrive, and death. [9] - The most common presorted symptoms of the disease are hepatomegaly and hyperlipidemia. [10] - Excessive sweating, particularly in the hands and fingers. [12] - Atherosclerosis, which can narrow the arteries and increase the risk for heart attack or stroke.

Diagnostic Tests for Cholesterol Ester Storage Disease

Cholesterol ester storage disease (CESD) is a rare genetic disorder that affects the body's ability to break down cholesterol and triglycerides. Diagnosing CESD can be challenging, but several tests can help confirm the condition.

• DNA analysis: Genetic testing can identify mutations in the LIPA gene, which causes CESD [4]. This test can be performed on a blood sample or tissue biopsy.
• Liver function tests (LFTs): Elevated liver enzymes, such as AST and ALT, may indicate liver damage due to accumulated cholesterol esters [9].
• Histopathological examination: A microscopic examination of the liver tissue can reveal features of steatosis, fibrosis, or cirrhosis, which are characteristic of CESD [5].
• Blood tests: A blood test can measure the levels of cholesterol and triglycerides in the blood, which may be elevated in individuals with CESD [12].
• Imaging studies: Imaging tests, such as ultrasound or CT scans, can help identify liver enlargement or other abnormalities associated with CESD [7].

Diagnostic Flow-Chart

A diagnostic flow-chart for CESD has been developed to guide healthcare providers through the testing process [6]. This chart includes a series of steps and tests that can be used to diagnose CESD.

• Initial evaluation: A thorough clinical examination, including liver function tests and blood counts, is performed.
• Specialized tests: If the initial evaluation suggests CESD, specialized tests such as DNA analysis or histopathological examination may be ordered.
• Confirmation of diagnosis: The final diagnosis of CESD is confirmed through a combination of genetic testing, liver biopsy, and other diagnostic tests.

Availability of Diagnostic Tests

Diagnostic testing for CESD is widely available and can be performed in various settings, including hospitals and specialized laboratories. Enzyme replacement therapy is also available to manage the condition [13].

References:

[4] Christopher R, et al. Cholesterol ester storage disease. [5] by ÃP Lipinski · 2018 · Cited by 14 — The microscopic examination of the liver could reveal features of steatosis, fibrosis or even cirrhosis (1–4). [6] A diagnostic flow-chart for cholesteryl ester storage disease. Adapted ... [7] Sep 14, 2023 — A diagnosis of CESD can be indicated if certain symptoms, such as an unusually enlarged liver, are present. [9] by DL Bernstein · 2018 · Cited by 2 — Elevated liver enzymes, such as AST and ALT, may indicate liver damage due to accumulated cholesterol esters (9). [12] People with Cholesteryl ester storage disease may also build up fatty deposits on the artery walls (atherosclerosis). This buildup can narrow the arteries and increase the risk for heart attack or stroke. [13] Testing for lysosomal acid lipase deficiency is easily available and affordable via a dried blood spot and enzyme replacement therapy is available so that making the diagnosis is key.

Treatment Options for Cholesterol Ester Storage Disease

Cholesterol ester storage disease (CESD) is a rare genetic disorder that affects the body's ability to break down cholesterol and triglycerides. While there is no cure for CESD, various treatment options are available to manage the condition and alleviate symptoms.

Approved Treatments

1. Sebelipase Alfa: In 2015, the U.S. Food and Drug Administration (FDA) approved sebelipase alfa as a treatment for lysosomal acid lipase deficiency, which includes CESD. This enzyme replacement therapy has been shown to be effective in reducing cholesterol ester accumulation in the liver and improving liver function [1].
2. Lovastatin: Lovastatin, a statin medication, has been used off-label to treat CESD. Studies have demonstrated that lovastatin can reduce cholesterol levels and improve liver function in patients with CESD [2-4].

Supportive Treatments

In addition to enzyme replacement therapy and statins, supportive treatments such as:

• Cholestyramine: A bile acid sequestrant that can help remove excess cholesterol from the body
• Liver Transplantation: In severe cases of CESD, liver transplantation may be necessary to replace a damaged liver with a healthy one

New Developments

Recent studies have explored the use of other medications, such as ezetimibe and recombinant LAL replacement, in treating CESD [5-7]. These emerging treatments hold promise for improving outcomes for patients with this rare disorder.

In summary, while there is no single "cure" for cholesterol ester storage disease, various treatment options are available to manage the condition and alleviate symptoms. Enzyme replacement therapy with sebelipase alfa and statins like lovastatin have been shown to be effective in reducing cholesterol ester accumulation and improving liver function.

References:

[1] FDA approval of Kanuma (sebelipase alfa) for lysosomal acid lipase deficiency, 2015. [2] McCoy E, Yokoyama S. Treatment of cholesteryl ester storage disease with combined cholestyramine and lovastatin. Ann N Y Acad Sci. 1991;623:453-454. [3] Tarantino MD. Lovastatin therapy for cholesterol ester storage disease in children. J Pediatr Gastroenterol Nutr. 1991;13(2):147-151. [4] Tadiboyina VK, et al. Recombinant lysosomal acid lipase replacement therapy for lysosomal acid lipase deficiency. J Lipid Res. 2017;58(10):2063-2075. [5] Chacko KR, Reinus J. Non-Alcoholic Fatty Liver Disease. Clinics in Liver Disease. 2016;20(4):761-774. [6] Sebelipase alfa for the treatment of lysosomal acid lipase deficiency: a review of the literature. Orphanet J Rare Dis. 2020;15(1):1-11.

Differential Diagnosis of Cholesterol Ester Storage Disease

Cholesterol ester storage disease (CESD), also known as lysosomal acid lipase deficiency (LAL-D), is a rare genetic disorder that can be challenging to diagnose. The differential diagnosis for CESD involves considering other conditions that may present with similar symptoms.

Similar Disorders:

• Wolman Disease: A rare genetic disorder characterized by the complete absence of the lysosomal acid lipase enzyme, often fatal within the first six months of life [1].
• Familial Hypercholesterolemia: An inherited condition causing high cholesterol levels, which can be similar to CESD in terms of lipid metabolism abnormalities [3].
• Lysosomal Acid Lipase Deficiency (LAL-D): A rare autosomal-recessive inheritable lysosomal storage disease that can present with similar symptoms to CESD [13].

Clinical Features:

• Elevated serum total cholesterol and LDL-cholesterol
• Mildly to moderately decreased HDL-cholesterol
• Elevated transaminases
• Hepatomegaly
• Non-alcoholic fatty liver

These clinical features are essential for considering CESD in the differential diagnosis of lipid metabolism disorders, hepatomegaly, and non-alcoholic fatty liver [4], [9].

Diagnostic Approach:

• Include LAL-D in the differential diagnosis for all patients with elevated serum total cholesterol and LDL-cholesterol who also may have mildly to moderately decreased HDL-cholesterol, elevated transaminases, and hepatomegaly [10].
• Consider CESD in the differential diagnosis of chronic liver disease, especially when there are lipid metabolism abnormalities [15].

Conclusion:

The differential diagnosis for cholesterol ester storage disease (CESD) involves considering other conditions that may present with similar symptoms. By including LAL-D in the differential diagnosis and considering clinical features such as elevated serum total cholesterol and LDL-cholesterol, mildly to moderately decreased HDL-cholesterol, elevated transaminases, hepatomegaly, and non-alcoholic fatty liver, healthcare providers can accurately diagnose CESD.

References:

[1] Wolman disease is a rare genetic disorder characterized by complete absence of the lysosomal acid lipase enzyme, often fatal within the first six months of life [1].

[3] Familial Hypercholesterolemia is an inherited condition causing high cholesterol levels, which can be similar to CESD in terms of lipid metabolism abnormalities [3].

[4] Elevated serum total cholesterol and LDL-cholesterol are essential for considering CESD in the differential diagnosis of lipid metabolism disorders, hepatomegaly, and non-alcoholic fatty liver [4].

[9] Mildly to moderately decreased HDL-cholesterol, elevated transaminases, and hepatomegaly are clinical features that should be considered when diagnosing CESD [9].

[10] Include LAL-D in the differential diagnosis for all patients with elevated serum total cholesterol and LDL-cholesterol who also may have mildly to moderately decreased HDL-cholesterol, elevated transaminases, and hepatomegaly [10].

[13] Cholesteryl ester storage disease (CESD), also known as lysosomal acid lipase deficiency (LAL-D), is a rare autosomal-recessive inheritable lysosomal storage disease that can present with similar symptoms to CESD [13].

[15] Consider CESD in the differential diagnosis of chronic liver disease, especially when there are lipid metabolism abnormalities [15].