Understanding Familial Hypercholesterolemia: Genetics, Epidemiology, And Management

Introduction of Familial Hypercholesterolemia

Familial Hypercholesterolemia is a disorder that causes low-density lipoprotein or bad cholesterol levels to be very high¹. This genetic disorder is caused by a defect on chromosome 19. Familial Hypercholesterolemia first case was described a hundred years ago. Its inheritance from generation to generation was more implicit in the 1930’s by Carl Muller. The actual proof about it was unveiled in the 1960’s and 1970’s by Goldstein and Brown². In Australia there are estimated 65,000 people with FH while many are still undiagnosed. FH patients are mostly undertreated. Early detection, testing and adequate treatment can improve the outcome of the patient. Worldwide, heterozygous (He) forms are common (1 in 250) people and as a result the heterozygous FH affects an approximate of 1 in 160-300,000 of the populations worldwide⁷. European countries have a lower number of patients identified (<1%) while other countries the number is higher⁷. People with the disorder are unable to recycle the natural supply of cholesterol constantly produced by the body.

Therefore, for a person with FH, the cholesterol levels (LDL) get exceedingly higher³.  When LDL is not removed from the bloodstream properly by the liver, it elevates cholesterol in blood which leads to blockage of arteries of the heart or brain¹. This can lead to risks of heart attacks or disease³. High LDL level means too much LDL cholesterol in blood. Cholesterol reading of 130 to 159 mg/dL is borderline high while 160 to 189 mg/dL is high¹.  LDL levels should be lower than 100 mg/dL. 100 to 129 mg/dL levels are acceptable for those without health issues but not to people with heart disease or at risk of it. High LDL is bad because it leads to cholesterol build up in arteries causing atherosclerosis. There are two types of FH: Homozygous Familial Hypercholesterolemia (HoFC) and Heterozygous Familial Hypercholesterolemia (HeFH). HoFC is the most serious type causing heart disease but less common compared to HeFC. For a child with FH is at risk of heart attack, stroke and even death if not diagnosed early enough⁴. Such a condition puts pressure to the family financially and grief due to loss of a loved one. FH is causing a burden of cardiovascular diseases that have a high mortality rate. Diagnosing and treating people with FH will help reduce the dangers associated with it.

Gene mutation can either be hereditary or somatic. Hereditary mutation is where a child acquires germ line mutations that are present in the parent’s germ cells⁸. A fertilized egg receives DNA from both parents and if it has a mutation it is passed to the unborn. Somatic (acquired) mutations occur at some point in a person’s life and are present only in some cells. They can occur due to environmental changes like ultraviolet rays from the sun, or an error occurs during cell division⁸.  Genes are basic functional units that are inherited from parents through DNA. They contain a particular set of instructions for individual characteristics. Mutations are the alterations that occur in the DNA structure as a result of hereditary factors or environmental changes⁸.

Epidemiology of FH in Australia and Worldwide

Chromosomes are thread-like structures of nucleic acids and protein that carry DNA. Inborn errors of metabolism occur as a result of inherited deficiency of proteins that have receptor, enzymatic, carrier of structural roles. Enzymes are proteins that speed up the rate of chemical reactions that take place within the body cells⁸. Autosomal dominant is one of the ways a disorder can be passed down to the families. The mutated gene becomes a dominant gene². A recessive gene is a gene whose effects are masked by the dominant gene. A recessive gene occurs when a gene from both parents is the same. FH is autosomal dominant inherited condition such that a parent who carries an altered gene causing the condition has a 50% to pass the mutated gene to the 1 in 2 children². The altered gene is located on chromosome number 19 that contains information for LDL receptor responsible for clearing LDL from bloodstream⁶. Heterozygous FH is where a person inherits one copy of gene mutation causing FH from one of the parents. Homozygous FH is when a person inherits a mutated copy of the gene causing FH from both parents⁶.

Familial Hypercholesterolemia is passed through inheritance in an autosomal dominant manner. Parents pass the disorder to their children through their DNA that has genetic makeup. Genes carry physical and functional characteristics of an individual that they get from the parents⁹. Once a gene is mutated it can have mild or severe problems¹. Three different genes can be mutated in Homozygous Familial Hypercholesterolemia. LDL receptor is responsible for removing LDL-C from the blood. A mutated gene for LDL receptor will lead to increase of LDL-C in blood. Genes such as PCSK9 and APoB if also mutated can lower the removal of LDL-C from blood. A person with one of these mutated genes has HeFH and if he or she has two of them then it is HoFH^9,1. Cholesterol in bloodstream is carried in small packages called lipoproteins made up lipids on the inside and proteins outside. Cholesterol is carried throughout the body by LDL and HDL. Cholesterol carried by LDL is referred as bad since people with FH have high of LDL and cannot be removed from the bloodstream properly by the liver. This increases risks of heart attacks and heart disease¹. High density lipoprotein (HDL) is good cholesterol since it lowers a person’s risk of getting heart disease. The altered gene that causes FH is located on chromosome number 19. The gene contains information for LDL receptor that clears LDL cholesterol from the bloodstream³.

FH is diagnosed through laboratory testing and physical examination. Physical examination can diagnose xanthomas and xanthelasmas, and corneal arcus. Laboratory tests are blood test, genetic testing and studies of heart function⁵. Blood test may show an increase in cholesterol of above 300 mg/dl and LDL levels of above 200 mg/dl³. A stress test for heart studies may be abnormal and a genetic test can show a gene mutation. Signs and symptoms of FH are: xanthomas, xanthelasmas, angina, a family history of high LDL cholesterol and heart attacks, corneal arcus, increased and therapy-resistant levels of LDL, high levels of LDL-C. At an early age xanthomas may develop under the skin, over elbows, buttocks and knees and in the tendons⁵. These can sometimes occur in infancy. Heart attacks and death can happen before age 30. Heart attacks and stroke can lead to diagnosis of FH⁵.

Health impacts and experiences of FH for an individual and their families

For treatment of an individual with heterozygous FH, the first step is changing the diet by reducing the amount of fat eaten to 30% of the total daily calories⁵. This is possible through limiting the amount of pork, beef and lamb in diet. Cutting out whole milk, fatty cheeses, butter, oils like coconut and palm oils. Eliminating organ meat, egg yolks and other saturated animal fatsfrom the diet³. Nutrition and dietary counseling will also help people make changes in their eating habits. Exercises that help in losing weight will cut out levels of cholesterol. Either these interventions cannot lower cholesterol levels alone³. Medications that are currently used are statins, gemfibrozil, bile acid sequestrant resins (i.echolestyramine), fenofibrate, ezetemibe and nicotinic acid (niacin). Individuals with HoFH condition it is life-threatening if not treated at an early age preferably childhood⁶. Drug therapies alone cannot lower LDL cholesterol levels to a considerate level. The condition requires medication and specialized treatments to lower LDL-C. The person may also require a process to get rid of LDL from the bloodstream or an invasive surgery like liver transplant⁶.

Children with FH start building up cholesterol in their arteries as toddlers and by age 12 many have measurable atherosclerosis⁴. First test should be between ages 9-11 and have the test again after every five years⁴. A test can be done at age 2 if a family has a history of high LDL-C. 20 years and above should have the test every five years. Men aged 45-65 and women of 55 to 65 years should have a test every 1 to 2 years.  Treatment can be carried out with medications to lower risks associated with FH and lower chances of heart disease⁹. Exercise stress testing of adults is advisable and other forms of non-invasive testing to help in early identification of atherosclerosis. Exercise, diet and avoidance of smoking should be evaluated and treated. FH Australia developed an all-inclusive model of care which has now become a template for international recommendations⁷. The Australian guidelines are more detailed and compatible than the UK NICE and other European guidelines for FH⁷. Healthcare research is always producing large amounts of research and updated methods of treatment and care for patients where when put in practice have the potential to save lives and improve the patients’ quality of life. Recent advances in genomics have boosted the knowledge of basis of high cholesterol and new medications are available, there are knowledge gaps that are arising and its awareness and control⁹.

There are still gaps in awareness of and control of FH. There is an aim of developing an electronic phenotypic algorithm for quick identification of FH cases. This will spread awareness and control of the condition. More campaigns to create awareness should be called to get more people tested and treatment for those diagnosed with the condition. This will also help reduce the cardiovascular diseases and mortality rates occurring as a result of the condition.

Conclusion:

Familial Hypercholesterolemia is a genetically hereditary condition that causes high levels of LDL cholesterol levels. Too much cholesterol in the blood stream builds up on the walls of the arteries increasing the risks of heart disease. The two main lipoprotein carrying cholesterol throughout the body are LDL and HDL. HDL is good cholesterol while LDL IS bad cholesterol which increases risk of heart attacks and heart disease. The condition is inherited through autosomal dominant manner. Gene mutation causes the disorder. People can have one or two mutated genes. This increases the blood cholesterol level. Dietary, treatment and exercises will lower levels of cholesterol.

References:

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