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.

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].

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].

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].

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%.

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].

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].

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

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].

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.

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