Cholerstinester storage disease is a lysosomal storage disease and inborn error of metabolism with a genetic basis. The disease is hereditary and is caused by a genetic mutation in the coding genes for lysosomal acid lipase. Symptomatic treatment of patients is conservative medication or enzyme replacement therapy steps.
What is cholesterol ester storage disease?
The group of lysosomal storage diseases includes a number of congenital diseases that result from inadequate or defective activity of the so-called lysosomes. All diseases in the group are metabolic diseases. One such disease is cholesterol ester storage disease, often abbreviated as CESD. Like all lysosomal storage diseases, CESD is based on a lack of activity of certain lysosomes. The lack of activity in this disease relates to lysosomal acid lipase, which in a healthy individual causes cholesteryl esters and triacylglyceride to be broken down. Cholerestinester storage disease is an extremely rare metabolic disorder and is associated with heritability. In this context, the mode of inheritance corresponds to autosomal recessive inheritance. The disease belongs to the group of inborn errors of metabolism. However, the manifestation of the first symptoms does not have to occur immediately after birth. The primary cause of the disease is a genetic mutation. A disease with a similar genetic mutation is Wolman’s disease. In contrast to this disease, cholesterol ester storage disease is characterized by a much milder course because residual activity of lysosomal acid lipase is preserved and can accomplish cholesterol ester degradation, at least outside the liver.
Causes
Patients with cholerestine ester storage disease have an enzyme defect in lysosomal acid lipase. This defect results in decreased degradation of cholerestine ester. This results in an accumulation of cholesterol esters and the equally poorly degraded triglycerides during the course of the disease. The coding gene for acid lipase is located in the DNA on chromosome 10 in gene locus q23.2 to 23.3. Ten exons make up the gene. The cause of choleretin ester storage disease is a nonsense or missense mutation of the exons involved. Frameshifts or skipping of certain exons may also be causative. The mutated gene product shows reduced activity, so that hardly any lipids of the lysosome can penetrate into the cytoplasm. Thus, the control loop for the regulation of intracellular cholesterol concentrations is interrupted. An intracellular low cholesterol concentration develops and brings endogenous cholesterol synthesis and LDL receptor activity to an upregulation. As a consequence, the lysosome takes up endocytosed cholesterol. Due to endogenous synthesis of cholesterol, cells are overloaded and lipid vacuoles form. The vacuoles lead to loss of function of individual cells, trigger fibrosis, and condition cell death.
Symptoms, complaints, and signs
Cholerestinester storage disease is characterized by a distinctive complex of clinical symptoms. Abnormalities of the liver are particularly typical abnormalities. As an organ, the liver is significantly involved in cholsterol metabolism, which explains the preferential initial manifestation of the disease in the liver. In patients with cholerestinester storage disease, the symptomatology manifests in most cases much later than in patients with Wolman disease. In the latter, the first symptoms usually manifest more or less immediately after birth. In contrast, patients with cholerestinester storage disease may remain asymptomatic for a long time. The leading symptom is hepatomegaly. The liver swells and develops into a fatty liver as storage progresses. In addition, hypercholesterolemia occurs in most cases. This hypercholesterolemia corresponds to a lipid metabolism disorder due to elevated blood cholesterol levels. These symptoms are usually associated with hyperlipidemia and decreased HDL concentration. Apart from the swelling of the liver and the loss of its function, most of the symptoms can only be diagnosed by laboratory diagnostics.
Diagnosis
Diagnosis of cholerestinester storage disease requires laboratory blood analysis, which can detect the altered lipid pattern and demonstrate foam cells that occur. In addition, a liver biopsy showing massive lysosmal accumulations can be performed as part of the diagnostic process. Differentially, the disease must be differentiated from other lysosomal storage diseases during the diagnostic process. Usually, this differentiation is done in the context of enzymatic activity tests. Genetic testing to identify the mutation is rather rarely used for delineation.
Complications
Cholesterol ester storage disease can result in a variety of symptoms and complications, depending primarily on the severity of the disease. In most cases, however, the liver is affected. In many patients, the first signs of cholesterol ester storage disease appear immediately after birth, so that, for example, the liver is swollen or when it develops into a so-called fatty liver in the further course of the disease. Most of the time, patients also suffer from pain and a stinging sensation due to the swelling. Diagnosis is usually relatively easy with a blood test, so there is no delay in diagnosis. Unfortunately, a causal therapy and treatment of cholesterol ester storage disease is not possible, so that mainly the symptoms have to be limited. In this case, a reduced absorption of cholesterol is achieved. However, the patient is dependent on taking medication for the rest of his life. Otherwise, cholesterol ester storage disease does not cause any further symptoms or complications. Life expectancy is also not reduced during therapy. The patient’s everyday life is rarely restricted by the disease. However, when planning to have children, the likelihood of the disease worshipping should be investigated.
When should one go to the doctor?
Cholesterol ester storage disease is usually detected immediately after birth. Typical signs that indicate the disease and must be clarified and treated are a swollen liver and, as it progresses, signs of fatty liver. If the child complains of stabbing pain in the area of the liver, the pediatrician should be consulted immediately. This is especially true if other complaints are added that point to cholesterol ester storage disease. In case of severe complications, emergency medical services should be contacted in any case. Although the disease rarely causes life-threatening symptoms, chronic liver disease may develop under certain circumstances. For this reason, a doctor should be consulted at the first signs of cholesterol ester storage disease. If cases of the disease are already known in the family, an immediate examination after birth is recommended. In some circumstances, the disease can also be detected prenatally. The physician will then discuss with the parents what further measures may be considered as part of treatment.
Treatment and therapy
Cholerestinester storage disease is due to a genetic defect. Therefore, no causative therapeutic steps are available to treat patients to date. Causative therapy would only be possible in the context of gene therapy approaches. However, gene therapy has not yet reached the clinical phase. Therefore, storage disease is still considered incurable and is treated exclusively symptomatically. Symptomatic therapy focuses on a reduced absorption of cholesterol. For this purpose, the intestinal cholesterol absorption of the patients is conservatively inhibited with drugs. Drugs such as colestyramine and ezetimibe are suitable for inhibition. In addition, patients usually receive statins, which result in inhibition of HMG-CoA reductase. In the recent past, additional new treatment options have become established, most notably enzyme replacement therapies. For patients with cholerestinester storage disease, the enzyme sebelipase alfa plays a particularly important role. Enzyme replacement therapies with this enzyme are currently being used in clinical trials and were approved and positively evaluated by the European Medicines Agency last year.
Outlook and prognosis
Cholesterol ester storage disease has an unfavorable prognosis. The disease is not considered curable and can lead to difficult complications.The recessively hereditary disease is treated symptomatically by physicians, since for legal reasons intervention in the genetics of humans is currently not permitted. The manifestation of the disease is individual and thus different for each patient. Accordingly, there is also no uniform treatment plan. As soon as the liver is affected, the prospect of improvement decreases considerably. Swelling of the liver or fatty liver can lead to other diseases. Often there is increased inflammation or cirrhosis of the liver. At this stage, alleviation of symptoms is almost impossible. The sufferer is threatened with liver failure and thus premature death. Patients whose livers are not damaged are in much better health. As long as they follow the doctors’ guidelines and avoid the intake of cholesterol-containing products in addition to drug treatment, they experience a good quality of life despite the storage disease. However, since the treatment is a long-term therapy, the health condition deteriorates within a short period of time once the medication is discontinued. An unhealthy lifestyle also has an immediate negative impact on the patient’s well-being.
Prevention
Cholerestinester storage disease is a genetic disease. Because no external factors are known to be causative, the disease can so far be prevented at best and exclusively by genetic counseling during the family planning phase. However, new mutations cannot be ruled out even with this approach.
Follow-up
In most cases, no special aftercare measures are available to the affected person for cholesterol ester storage disease. In this case, the patient is primarily dependent on a rapid diagnosis so that the symptoms can be properly alleviated, as this also does not allow self-healing to occur. Therefore, the affected person should contact a doctor as soon as the first symptoms and complaints appear, in order to avert a further worsening of the symptoms. Since this is a genetic disease, genetic testing and counseling should always be performed if the patient wishes to have children in order to prevent a recurrence of cholesterol ester storage disease. In most cases, the disease is treated by taking medication. The affected person should ensure that the medication is taken regularly and in the correct dosage so that the symptoms are permanently alleviated. If there are any uncertainties or questions, a doctor should be consulted first. Many patients are dependent on the help and support of friends and family due to cholesterol ester storage disease. Contact with others affected by the disease can also be very useful.
This is what you can do yourself
Cholesterol ester storage disease is a genetic disorder. Therefore, there are currently neither conventional, nor alternative methods to treat the disease causally. Accordingly, there are no self-help measures available to combat the condition causally. However, patients can still make an important contribution to preventing the progression of the disease and serious consequential damage, especially to the liver. A low-cholesterol diet is of central importance. Patients should obtain comprehensive and competent information about the special dietary requirements of cholesterol ester storage disease. The attending physician is not always the best possible contact in this regard, as nutritional issues still play little role in the training of physicians. Those affected should therefore consult a nutritionist or an ecotrophologist. In general, cholesterol is found exclusively in foods of animal origin. A changeover to a vegan diet is therefore advisable for those affected. In any case, animal foods that are particularly rich in cholesterol should be avoided at all costs. These include in particular fatty meat, sausages, offal, eggs, butter, cream and whole milk. Eggs are often consumed in a hidden way. Patients are often unaware that many pasta products, especially pasta and pastries, as well as convenience foods and mayonnaise contain large amounts of eggs and correspondingly high amounts of cholesterol.