What is Cholesteryl Ester Storage Disease?

​​​​​​Cholesteryl Ester Storage Disease (CESD) is a rare autosomal recessive multisystem condition that belongs to the lysosomal storage disorders family.

The liver is one of the most common sites of Cholesteryl Ester Storage Disease
The liver is one of the most common sites of Cholesteryl Ester Storage Disease. Image Credit: Marko Aliaksandr/Shutterstock.com

Because of a lack of the enzyme Lysosomal Acid Lipase (LAL/ LIPA), cholesteryl esters and triglycerides accumulate in various organs. CESD can manifest itself at any age, from childhood to adulthood. In general, the clinical symptoms are severe in babies and milder in adults.

The liver is one of the most common sites of involvement, with symptoms ranging from isolated hepatomegaly to cirrhosis of the liver. An aberrant lipid profile, cholesterol crystal buildup in internal organs, and impaired acid lipase activity in leukocytes all point to the diagnosis.

Causes and symptoms

CESD occurs due to mutations in the LIPA (lysosomal acid lipase) gene. Mutations in the LIPA gene on chromosome 10q23.2-q23.3 can cause a benign disorder CESD, which causes a reduction in enzymatic activity and a massive accumulation of cholesteryl esters and triglycerides in many body tissues

Alternatively, it can cause a more serious disorder, CESD, which causes a massive accumulation of cholesteryl esters and triglycerides in many body tissues.

CESD has a wide range of symptoms and severity. Some people acquire symptoms in childhood, while others have extremely mild cases with few signs. Others may not show any signs at all and continue undetected until they reach adulthood.

Patients with severe signs, such as diarrhea, failure to thrive, emesis, abdominal distension, and even adrenal calcifications, may show in infancy but survive into adolescence or adulthood. Hepatomegaly and liver dysfunction, as well as type IIb dysliproteinemia, are common symptoms.

Adrenalomegaly (abnormal enlargement of the adrenal glands) can also develop in a few people. Feeding difficulties in infants might include frequent vomiting, diarrhea, abdominal swelling, and a failure to gain weight. Liver failure and/or subsequent accelerated atherosclerotic disease are common causes of CESD-related mortality.

Lysosomal storage diseases

Lysosomal storage diseases (LSDs) are a group of about 50 disorders caused by lysosomal enzyme or protein deficiencies. By digesting and recycling lipids and macromolecules through the endosomal-autophagic-lysosomal system, lysosomes help to maintain overall cell homeostasis.

A lysosomal enzyme or protein shortage at any stage in the lysosomal breakdown pathway might result in lipid or macromolecule buildup upstream of the defect.

Thus, depending on the nature of the macromolecule accumulating, LSDs as a set of disorders can result in a wide range of clinical manifestations and underlying cellular abnormalities. There are approximately 50 LSDs which have a prevalence of 1 in every 5,000-10,000 live births (as a group).

Wolman disease and cholesteryl ester storage disease

Wolman disease (WD) and cholesteryl ester storage disease (CESD) are lysosomal storage diseases (LSDs) caused by mutations in the LIPA gene that induce a deficit in lysosomal acid lipase (LAL).

In WD, LAL function is fully lost, whereas, in CESD, some residual activity remains. Both are rare disorders, with a WD incidence rate of fewer than 1/100,000 births and a CESD incidence rate of roughly 2.5/100,000 births. CESD has a milder and more varied clinical appearance than WD.


The LIPA gene is 36kb long and has 10 exons and 9 introns. Missense mutations in the LIPA gene are the most common cause of CESD. The G -> A mutation at position -1 of the exon 8 splice donor site (c.894G>A; E8SJM) is a frequent CESD mutation that accounts for about 60% of all CESD cases.

This mutation results in a transcript with no LAL activity; nonetheless, the deficiency allows for the normal splicing of 3-5 percent of LAL.

What are Lysosomal Storage Diseases?


CESD is more difficult to diagnose and may be underdiagnosed due to the wide range of clinical characteristics it can present. Although there have been few cases of CESD published, it is estimated that 2.5/100,000 people in some European groups carry biallelic LIPA mutations that cause CESD. CESD is often misdiagnosed, particularly in patients of European heritage.

Diagnosis and treatment

A diagnosis of CESD can be indicated if certain symptoms, such as an unusually enlarged liver, are present. As a result, a thorough clinical examination, a thorough patient history (including family history), and specialist diagnostics are required.

Measurement of LAL enzymatic activity in leukocytes in a blood sample or on a dried blood spot is the first test recommended for establishing a diagnosis of LAL-D, followed by targeted DNA sequencing of LIPA to identify the pathogenic variation (s).

Patients with CESD have had success with liver transplants. Given that cirrhosis of the liver is the disease pathology that causes early death, liver transplantation is a sensible medical technique to prolong the patient's life.

Patient survival has been reported to range from 2 to 7 years after surgery, according to the literature. The FDA recently approved ERT (enzyme replacement therapy) for the treatment of patients with LAL deficiency. Small molecule medicines, such as additional LSDs, are still needed to improve CESD treatment in the future.

Recent breakthroughs in iPSC (induced pluripotent stem cell) technology have resulted in a new patient-derived cell-based disease model system for CESD.

The development of new small molecule therapeutics for both diseases will be aided by high throughput screening of compound collections with phenotypic disease models of CESD created using iPSC technology.


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  • Lipiński P, Ługowska A, Zakharova EY, et al. (2018). Diagnostic Algorithm for Cholesteryl Ester Storage Disease: Clinical Presentation in 19 Polish Patients. Journal of Pediatric Gastroenterology and Nutrition, 67(4), 452–457. doi:10.1097/MPG.0000000000002084
  • Pericleous M, Kelly C, Wang T, et al. (2017). Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency. The Lancet Gastroenterology & Hepatology, 2(9), 670–679. doi:10.1016/S2468-1253(17)30052-3
  • Pant M, & Oshima K (2017). Cholesteryl Ester Storage Disease: An underdiagnosed cause of cirrhosis in adults. Annals of Diagnostic Pathology, 31, 66–70. doi:10.1016/j.anndiagpath.2017.02.005
  • Aguisanda F, Thorne N, & Zheng W (2017). Targeting Wolman Disease and Cholesteryl Ester Storage Disease: Disease Pathogenesis and Therapeutic Development. Current Chemical Genomics and Translational Medicine, 11, 1–18. doi:10.2174/2213988501711010001
  • Freudenberg F, Bufler P, Ensenauer R, et al. (2013). Cholesteryl ester storage disease: an easily missed diagnosis in oligosymptomatic children. Zeitschrift fur Gastroenterologie, 51(10), 1184–1187. doi:10.1055/s-0033-1350463
  • Bernstein DL, Hülkova H, Bialer MG, et al. (2013). Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. Journal of Hepatology, 58(6), 1230–1243. doi:10.1016/j.jhep.2013.02.014


Further Reading

Last Updated: Sep 14, 2023


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