Understanding Familial Hypercholesterolemia: A Detailed Report

This report provides a comprehensive overview of Familial Hypercholesterolemia (FH), a genetic disorder characterized by high levels of low-density lipoprotein (LDL) cholesterol. It begins with an introduction to FH, tracing its history and epidemiology in Australia and worldwide, highlighting its impact on public health. The report delves into the causes of FH, explaining the role of genes, mutations, and chromosomes, including the distinction between autosomal dominant and recessive inheritance. It clarifies the differences between heterozygous and homozygous forms of FH and elaborates on the roles of LDL and high-density lipoprotein (HDL) cholesterol. The report discusses the health impacts of FH, including premature cardiovascular diseases and mortality, and emphasizes the importance of early diagnosis and treatment. It outlines the clinical symptoms, prognosis, and available treatment options, including dietary management, medications, and advanced therapies like liver transplants. The report also covers the current gaps in awareness and control of FH, suggesting recommendations for improved detection and management, including electronic phenotypic algorithms and awareness campaigns. Finally, the report concludes by summarizing the key aspects of FH, emphasizing the need for proactive measures to mitigate its impact.

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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.
Genetic background, principles and process
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. 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 gene 2. 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 HoFH9,1. 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.
Clinical symptoms and prognosis
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.
Treatment and dietary management
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.
Recommendations
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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