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Cholesterol Ester Storage Disease

Cholesteryl Ester Storage Disease

Cholesterol ester storage disease (CESD), which may also be called cholesteryl ester storage disease, is caused by lysosomal acid lipase deficiency of genetic origin. This enzyme is required for the breakdown of cholesteryl esters and triglycerides into cholesterol and fatty acids. In patients suffering from CESD, the former accumulate in liver, spleen, and macrophages throughout the body. This condition predisposes for liver failure and atherosclerosis. The disorder is inherited in an autosomal recessive manner.


Presentation

Contrary to Wolman disease (see that term), CESD is a late-onset, progressive disorder. First symptoms may be noted in infancy, childhood, or adulthood, depending on the degree of residual enzyme activity [1]. The mean age of onset is five years, with about two thirds of all cases becoming apparent before the age of twelve [2]. As a general rule, the earlier the onset, the more rapid progression is to be expected [3].

In more severe cases, there is some clinical overlap with Wolman disease and patients may suffer from vomiting and diarrhea, abdominal distension, and failure to thrive. Other patients present with palpable hepatomegaly or hepatosplenomegaly and associated symptoms like loss of appetite, abdominal pain and lethargy. Others remain asymptomatic and are only diagnosed following laboratory analyses of blood samples with abnormal results: Biochemical analyses of CESD patients reveal elevated serum transaminases and increased LDL cholesterol and triglycerides. HDL cholesterol concentrations are usually within or even below reference ranges [1]. If liver biopsy samples are obtained, excess lipid in hepatocytes and Kupffer cells can easily be recognized. Over the course of the disease, an initial microvesicular steatosis develops into liver fibrosis and micronodular cirrhosis [3]. Of note, a liver biopsy is not mandatory for the diagnosis of CESD.

As can be seen, the clincial presentation is highly variable. This fact becomes even more clear if it is considered that symptoms may not only result from an impairment of liver function, but may also be due to excess lipid storage in other organs. For instance, CESD patients may suffer from malabsorption or cardiovascular disease like coronary heart disease or stroke at an early age. Adrenal calcifications may also be detected.

Coronary Artery Disease
  • Actually, the screening of the E8SJM mutation has been commonly applied in studies of prevalence [ 18 ], and also when testing the contribution of a reduced LAL activity on the risk of dyslipidemia, myocardial infarction or coronary artery disease [ 19[journals.plos.org]
Death in Childhood
  • This disease can present early and lead to death in childhood or adolescence due to cirrhosis of the liver, or it may have a late onset with survival into adulthood.[sema4genomics.com]
Thyroid Nodule
  • MORPHOLOGY OF THE PITUITARY 19 THE OPTIC CHIASM IN ENDOCRINOLOGIC 204 PARANEOPLASTIC ENDOCRINE 223 SEX HORMONES AND HUMAN 219 APPROACH TO THE PATIENT WITH 37 ADVERSE EFFECTS OF IODIDE 360 MORPHOLOGY OF THE THYROID 38 NONTOXIC GOITER 366 SYNTHESIS AND 39 THE THYROID[books.google.com]
Splenomegaly
  • Disease definition Cholesteryl ester storage disease (CESD) is a very rare, late-onset, genetic endocrine disease characterized by deficient or inactive lysosomal acid lipase (LAL) causing lipid build-up, which leads to atherosclerosis, hepatomegaly, splenomegaly[orpha.net]
  • Criteria Inclusion Criteria: Age between 18-80 years; BMI 25-40; Fatty liver disease (bright liver, hepatomegaly by ultrasound (Liver span 15 cm mid clavicle line), splenomegaly ( 13 cm) or both.[clinicaltrials.gov]
  • Hepatomegaly was present in 99.3% of patients; 74% also had splenomegaly. When reported, most patients had elevated serum total cholesterol, LDL-cholesterol, triglycerides, and transaminases (AST, ALT, or both), while HDL-cholesterol was decreased.[ncbi.nlm.nih.gov]
  • […] under: Cholesteryl ester storage disease is is a type of lysosomal acid lipase deficiency. 0003124 Hypertriglyceridemia Increased plasma triglycerides Increased serum triglycerides Increased triglycerides [ more ] 0002155 Nausea and vomiting 0002017 Splenomegaly[rarediseases.info.nih.gov]
Massive Splenomegaly
  • Cholesteryl ester storage disease: a patient with massive splenomegaly and splenic abscess. Am J Gastroenterol . 1988; 83 :687-692. [ PubMed ] 6. Elleder M , Chlumská A, Hyánek J, Poupĕtová H, Ledvinová J, Maas S, Lohse P.[wjgnet.com]
Recurrent Diarrhea
  • We report about the unusual case of a 41-year-old woman who had been suffering from recurrent diarrhea since early childhood and was referred to the hospital during a severe episode of diarrhea and ensuing weight loss.[wjgnet.com]
Hepatomegaly
  • Clinical manifestations varied from neonatal cholestasis to asymptomatic hepatomegaly. Hepatic histology showed lipid vacuoles and cholesterol ester storage in hepatocytes and Kupffer cells.[ncbi.nlm.nih.gov]
  • The third affected sibling, followed to 13 years of age, has hepatomegaly, hyperlipidemia, short stature, adrenal calcification, and acid lipase deficiency. Leukocyte extracts demonstrated deficiency of acid lipase in this patient.[ncbi.nlm.nih.gov]
  • An adult patient is described with hepatomegaly and sea-blue histiocytes in the bone marrow. A diagnosis of cholesterol ester storage disease was established following enzyme and lipid analyses on liver biopsy and cultured skin fibroblasts.[ncbi.nlm.nih.gov]
  • CESD patients present in childhood with hepatomegaly and dyslipidemia characterized by elevated total and low-density lipoprotein cholesterol (LDL-C), with elevated triglycerides and depressed high-density lipoprotein cholesterol (HDL-C).[ncbi.nlm.nih.gov]
  • The clinical findings in both patients were confined to moderate well tolerated hepatomegaly, hyperlipoproteinaemia of IIb type and xanthelasmata. Acid lipase activity was markedly deficient in peripheral leukocytes and cultured fibroblasts.[ncbi.nlm.nih.gov]
Hepatosplenomegaly
  • A 5-year and 4-month old Thai female with hepatosplenomegaly and hypercholesterolemia was diagnosed to have this disease by light and electron microscopic studies of the liver tissue from open biopsy.[ncbi.nlm.nih.gov]
  • Two siblings manifested with hepatosplenomegaly, ptosis, and bilateral external ophthalmoplegia. Evaluation revealed hyperlipidemia and bilateral adrenal calcifications.[ncbi.nlm.nih.gov]
  • Since the residual LAL activity is higher and the clinical phenotype based on plasma lipid values and severity of hepatosplenomegaly is milder in this case than in a previously studied case who was homozygous for the E8SJM allele, we conclude that the[ncbi.nlm.nih.gov]
  • ·les·ter·ol es·ter stor·age dis·ease [MIM*278000] a lipidosis caused by a deficiency of lysosomal acid lipase activity resulting in widespread accumulation of cholesterol esters and triglycerides in viscera with xanthomatosis, adrenal calcification, hepatosplenomegaly[medical-dictionary.thefreedictionary.com]
  • Patients of 3 months to 18 years of age at the time of enrolment who have unexplained transaminase elevation (serum alanine aminotransferase (ALT) levels 1.5 times the upper limit of normal) for more than 3 months and/or unexplained hepatomegaly or hepatosplenomegaly[centerwatch.com]
Hydrops Fetalis
  • While Wolman disease has an infaust prognosis and leads to hydrops fetalis and congenital ascites as well as an abnormal neurological development, CESD presents as the milder form due to a residual enzymatic activity of approximately 3% which results[wjgnet.com]
Long Arm
  • This enzyme is encoded by the LIPA gene, which is located on the long arm of chromosome 10. The disease is inherited in an autosomal recessive pattern, i.e., affected individuals carry two defective alleles.[symptoma.com]
Neonate-Onset
  • Residual enzyme activity determines the severity of the disease: While the near-total absence of functional lysosomal acid lipase results in a neonatal-onset, fulminant form of CESD that is also known as Wolman disease, the term CESD is usually reserved[symptoma.com]

Workup

CESD-associated hepatopathy may be mistaken for viral hepatitis or non-alcoholic fatty liver disease, specifically for non-alcoholic steatohepatitis. To rule out these differential diagnoses, molecular biological and serological tests should be performed. Due to the relatively high incidence of these disorders, the respective analyses are usually carried out before a thorough genetic workup is started [3].

Disturbances of low-density lipoprotein metabolism may be triggered by a variety of gene mutations, with sequence anomalies interfering with the function of the low-density lipoprotein receptor being the most common ones. The latter cause familial hypercholesterolemia, which is inherited in an autosomal dominant manner. It should thus be possible to distinguish it from CESD after obtaining the patient's family history. Nevertheless, lysosomal acid lipase deficiency has occasionally been observed in individuals diagnosed with familial hypercholesterolemia and cases of autosomal recessive familial hypercholesterolemia have also been described [4] [5]. It is therefore recommendable to test for a variety of gene defects in case of hypercholesterolemia and negativity for familial hypercholesterolemia-associated mutations. Gene panel sequencing is the approach of choice to detect rare causes of hereditary liver disease in the absence of any concrete suspicion.

Enzyme activity measurements may either be carried out to confirm the pathogenicity of LIPA mutations detected by means of gene panel sequencing, or they may be realized in advance. Indeed, the latter represents the more direct approach to CESD diagnosis, but requires a corresponding suspicion. While very low levels of lysosomal acid lipase activity are considered diagnostic for CESD, intermediate results may not allow for an immediate diagnosis: They need to be confirmed by identifying the causal gene defect. Peripheral blood leukocytes, dried blood spots, skin fibroblasts and hepatocytes are suitable for the determination of lysosomal acid lipase activity.

Because CESD follows a progressive course, patients should undergo regular follow-ups to monitor disease evolution. Laboratory analyses of blood samples including liver function tests and lipid profiles should be carried out annually. Diagnostic imaging is recommended to evaluate the condition of liver, spleen, and other organ systems [3].

Acanthocytes
  • Peripheral blood showed macrocytic anemia with mild neutropenia, thrombocytopenia, and acanthocytes. Approximately 20% of lymphocytes demonstrated between 1 and 7 cytoplasmic vacuoles (panels A-C; May–Grünwald–Giemsa stain).[bloodjournal.org]
Abnormal Thyroid Function Test
  • THYROID FUNCTION TEST 47 THYROID DISORDERS OF INFANCY 462 P A RT IV CALCIUM AND BONE METABOLISM 473 MORPHOLOGY OF THE PARATHYROID 51 PARATHYROID HORMONE 497 PHYSIOLOGY OF CALCIUM 52 PARATHYROID HORMONERELATED 512 CLINICAL APPLICATION OF BONE MINERAL[books.google.com]
Macrocytic Anemia
  • Peripheral blood showed macrocytic anemia with mild neutropenia, thrombocytopenia, and acanthocytes. Approximately 20% of lymphocytes demonstrated between 1 and 7 cytoplasmic vacuoles (panels A-C; May–Grünwald–Giemsa stain).[bloodjournal.org]
Liver Biopsy
  • AIMS: To identify reliable criteria with which to improve the diagnosis of lysosomal acid lipase (LAL) deficiency of the cholesterol ester storage disease (CESD) type in liver biopsies.[ncbi.nlm.nih.gov]
  • A diagnosis of cholesterol ester storage disease was established following enzyme and lipid analyses on liver biopsy and cultured skin fibroblasts.[ncbi.nlm.nih.gov]
  • The younger sister had liver biopsies before and after 6 months of lovastatin therapy to assess hepatic cholesterol stores.[ncbi.nlm.nih.gov]
  • Diagnoses were based on liver biopsies, LAL deficiency and/or LAL gene (LIPA) mutations. Hepatomegaly was present in 99.3% of patients; 74% also had splenomegaly.[ncbi.nlm.nih.gov]
  • Of note, a liver biopsy is not mandatory for the diagnosis of CESD. As can be seen, the clincial presentation is highly variable.[symptoma.com]

Treatment

The primary aim of CESD therapy has long since been to lower plasma lipid levels. This has been achieved by means of applying 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, usually referred to as HMG-CoA reductase inhibitors or simply statins. However, it has been pointed out that this way, the reduction of plasma lipid concentrations may only be obtained at the expense of cholesteryl ester and triglyceride storage in tissues, thereby possibly even favoring liver failure [3]. Enzyme replacement therapy has been proposed as a distinct approach to avoid that risk and in 2015, sebelipase alfa, a recombinant human lysosomal acid lipase, has been approved to treat CESD in Europe and North America [2]. Because since then little time has passed, long-term outcomes of sebelipase alfa therapy are not yet available, but interim results are highly promising [2] [6] [7].

Prognosis

The majority of plasma cholesterol is contained in low-density lipoproteins and high levels of LDL cholesterol constitute a major risk factor for cardiovascular disease. With regards to cholesterol esters stored elsewhere, lipid accumulation within lysosomes of hepatocytes may strongly interfere with liver function and eventually provoke liver failure. Before sebelipase alfa became available for CESD treatment, either disorder typically caused a considerable reduction of life quality or even the premature death of the affected individual. Today, there is hope that enzyme replacement therapy may increase the patient's life expectancy [6].

Etiology

CESD develops due to lysosomal acid lipase deficiency. This enzyme is encoded by the LIPA gene, which is located on the long arm of chromosome 10. The disease is inherited in an autosomal recessive pattern, i.e., affected individuals carry two defective alleles. Both homozygosity and compound heterozygosity may lead to the disease [8]. In fact, several dozen mutations in the LIPA gene have been described and are associated with distinct degrees of enzyme deficiency. Presumably, symptoms are to be expected in those with an enzyme activity of <10% [8]. Of note, patients suffering from Wolman disease typically show residual enzyme activites of <1%.

Epidemiology

As of 2013, a total of 206 cases has been reported in literature - 71 pediatric cases and 135 adult cases [9]. However, there is a general consensus in that the disease is severely underdiagnosed. This particularly applies to the milder, even asymptomatic forms of the disease. Accordingly, estimates regarding the prevalence of the disease vary significantly and range between 1 in 40,000 and 1 in 300,000 individuals [8]. While lower estimates have been derived from clinical data, higher estimates are based on the frequency of potentially pathogenic variants of the LIPA gene and presumably include undiagnosed cases.

CESD is a pan-ethnic disease affecting men and women all over the world. The disease' prevalence may be slightly higher among European Caucasians because a relatively high carrier rate of about 1 in 200 has been determined for this population and the most common CESD-causing mutation, a splice junction mutation of exon 8 [10] [11]. Considering that this mutation is responsible for slightly more than half of all cases, the heterozygote frequency for all LIPA mutations may be estimated to almost 1 in 100 individuals [7].

Sex distribution
Age distribution

Pathophysiology

The cellular uptake of low-density lipoproteins including their cargo, namely cholesteryl esters, triglycerides, and other lipophilic substances, is mostly mediated by the low-density lipoprotein receptor. They are subsequently transported to the lysosomes, where cholesteryl esters and triglycerides are to be hydrolyzed. These reactions are catalyzed by the enzyme lysosomal acid lipase. In patients suffering from CESD, the activity of this enzyme is reduced to levels <10% of that measured in healthy individuals and consequently, cholesteryl esters and triglycerides cannot be broken down and accumulate within the lysosome.

Under physiological conditions, the degradation of cholesteryl esters and triglycerides yields cholesterol and free fatty acids. Because this process is disturbed in CESD patients, cytosolic cholesterol levels are well below reference ranges, causing the cell to take compensatory actions: On the one hand, the expression of the low-density lipoprotein receptor is augmented, and on the other hand, the endogenous production of cholesterol is enhanced. To facilitate the export of cholesterol from hepatocytes, increased quantities of apolipoprotein B are synthesized. More very light-density lipoproteins are released and subsequently transformed into low-density lipoproteins. At the same time, the expression of the ABCA1 transporter, which is required for the exocytosis of high-density lipoproteins, is reduced. This explains the laboratory results detailed above: permanent hypercholesterolemia, increased LDL cholesterol and decreased HDL cholesterol [2].

Prevention

Couples with a known family history of CESD or Wolman disease may benefit from genetic counseling. Additionally, the prenatal diagnosis of CESD is feasible.

Summary

CESD is a rare lysosomal storage disease caused by mutations in the gene encoding for lysosomal acid lipase. Distinct mutations have been described and associated with more or less severe reductions of enzyme activity. Residual enzyme activity determines the severity of the disease: While the near-total absence of functional lysosomal acid lipase results in a neonatal-onset, fulminant form of CESD that is also known as Wolman disease, the term CESD is usually reserved for milder cases [1] [12].

Lysosomal acid lipase has also been named cholesteryl ester hydrolase because its main function is the breakdown of cholesteryl esters contained in low-density lipoproteins. To a lesser extent, lysosomal acid lipase is also required for the degradation of triglycerides. Consequently, affected individuals suffer from excess cholesteryl ester and triglyceride storage, from hypercholesterolemia and hypertriglyceridemia and their possible consequences. Since both conditions are frequently encountered but patients are rarely checked for CESD-associated mutations, it has been speculated that CESD is largely underdiagnosed [8].

Cholesteryl esters and triglycerides are deposited in liver, spleen, kidneys, vessels and virtually all other organs that contain cells of the monocyte–macrophage cell lineage. The disease follows a progressive course and may eventually lead to organ failure, with liver failure being observed most commonly. Additionally, cardiovascular events may occur in affected individuals long before they would be expected due to age-related changes. In sum, CESD often decreases life quality and may even provoke premature death.

While lipid-lowering therapy and possibly hematopoietic stem cell or liver transplantation have long since been the only, but less than satisfactory treatment options, the recent approval of a recombinant human lysosomal acid lipase for CESD therapy gives new hope to those affected by this lysosomal storage disease [6].

Patient Information

Cholesterol ester storage disease (CESD) is a metabolic disorder associated with increased plasma cholesterol levels and an impairment of liver function. It is a genetic disorder inherited in an autosomal recessive manner and provoked by the near-total absence of an enzyme called lysosomal acid lipase. This enzyme is required for the breakdown of cholesterol esters after their uptake into liver cells and other cells throughout the whole body. Because the enzyme's activity is considerably reduced in those affected by CESD, cholesterol esters accumulate within the respective cells. Over the course of time, this process increasingly interferes with cell and organ function. In detail, CESD causes liver enlargement, possibly followed by liver fibrosis and cirrhosis, and atherosclerosis, which predisposes for coronary heart disease and stroke. Depending on the degree of residual enzyme activity, first symptoms and complications may appear in infancy, childhood, or adulthood.

Since 2015, a recombinant human lysosomal acid lipase has been available for the treatment of CESD. This recombinant enzyme replaces the missing or inactive enzyme in the patient's body and is able to lower plasma cholesterol concentrations as well as cholesterol ester storage in liver, vessels, and other organs. Although long-term results of such a therapy are not yet available, results obtained so far are highly promising and give new hope for better life quality and an increased life expectancy to those suffering from this rare disease.

References

Article

  1. Bernstein DL, Hülkova H, Bialer MG, Desnick RJ. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013; 58(6):1230-1243.
  2. Camarena C, Aldamiz-Echevarria LJ, Polo B, et al. Update on lysosomal acid lipase deficiency: Diagnosis, treatment and patient management. Med Clin (Barc). 2017; 148(9):429.e421-429.e410.
  3. Reiner Ž, Guardamagna O, Nair D, et al. Lysosomal acid lipase deficiency--an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis. 2014; 235(1):21-30.
  4. Sjouke B, Defesche JC, de Randamie JSE, Wiegman A, Fouchier SW, Hovingh GK. Sequencing for LIPA mutations in patients with a clinical diagnosis of familial hypercholesterolemia. Atherosclerosis. 2016; 251:263-265.
  5. Soutar AK, Naoumova RP. Autosomal recessive hypercholesterolemia. Semin Vasc Med. 2004; 4(3):241-248.
  6. Erwin AL. The role of sebelipase alfa in the treatment of lysosomal acid lipase deficiency. Therap Adv Gastroenterol. 2017; 10(7):553-562.
  7. Maciejko JJ. Managing Cardiovascular Risk in Lysosomal Acid Lipase Deficiency. Am J Cardiovasc Drugs. 2017; 17(3):217-231.
  8. Vinje T, Wierød L, Leren TP, Strom TB. Prevalence of cholesteryl ester storage disease among hypercholesterolemic subjects and functional characterization of mutations in the lysosomal acid lipase gene. Mol Genet Metab. 2017.
  9. Freudenberg F, Bufler P, Ensenauer R, Lohse P, Koletzko S. Cholesteryl ester storage disease: an easily missed diagnosis in oligosymptomatic children. Z Gastroenterol. 2013; 51(10):1184-1187.
  10. Muntoni S, Wiebusch H, Jansen-Rust M, et al. Prevalence of cholesteryl ester storage disease. Arterioscler Thromb Vasc Biol. 2007; 27(8):1866-1868.
  11. Scott SA, Liu B, Nazarenko I, et al. Frequency of the cholesteryl ester storage disease common LIPA E8SJM mutation (c.894G>A) in various racial and ethnic groups. Hepatology. 2013; 58(3):958-965.
  12. Anderson RA, Bryson GM, Parks JS. Lysosomal acid lipase mutations that determine phenotype in Wolman and cholesterol ester storage disease. Mol Genet Metab. 1999; 68(3):333-345.

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Last updated: 2019-07-11 20:04