Running Head: FAMILIAL HYPERCHOLESTEROLEMIA

Genetic Testing For Familial Hypercholesterolemia

Ashley Bennett, RN, BSN, FNP-S
Clemson University

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Abstract
Purpose: Familial hypercholesterolemia (FH) is an inherited autosomal dominant disease
causing a mutation that alters the bodys ability to eliminate cholesterol (Heart United Kingdom,
2015). The purpose of this paper is to discuss the pathophysiology of familial
hypercholesterolemia (FH), current diagnostic criteria used for diagnosis of FH, the costeffectiveness of genetic testing for diagnosis, and the clinical management of FH.
Methodology: An electronic search was performed using the search engines Google Scholar and
CINAHL. Fifteen articles were selected based on relevant content regarding familial
hypercholesterolemia and genetic testing.
Findings: Currently, there are many different criteria used to diagnosis FH. The research
showed the most cost-effective approach for diagnosis of FH was to perform genetic testing on
the index patient followed by cascade screening for relatives (Klose, et al., 2014, p. 525). The
first line treatment for FH patients is a statin medication (Ned & Sijbrands, 2011).
Conclusions: The literature reviewed showed the need for additional research to establish a
standard of care model for both diagnosis and treatment of FH.

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Genetic Testing For Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is an inherited autosomal dominant disease causing a
mutation that alters the bodys ability to eliminate cholesterol. There are three locations this
mutation can occur: low density lipoprotein receptor, apolipoprotein B, and proprotein
convertase subtilisin/kexin type 9. The most prevalent of the mutation occurs at the low density
lipoprotein (LDL) receptor gene and affects up to 80% of individuals with FH (Heart United
Kingdom, 2015). This mutation prohibits the liver from eliminating LDL from the blood, leading
to elevated blood cholesterol levels (National Institute of Health, 2014). Cholesterol levels
within a normal limit are essential for proper body function. High levels of serum cholesterol
cause an accumulation of cholesterol plaques within the blood vessels. This accumulation can
have severe and fatal complications such as cardiovascular disease (CVD), myocardial ischemia
(MI), and cerebrovascular accident (CVA) (The Familial Hypercholesterolemia Foundation
[TFHF], 2015).
Individuals with FH begin to develop this disease in utero. The disease is passed through
the genetic makeup of one or both parents. Individuals that inherit a mutated gene from one
parent have Heterozygous FH (HeFH) and individuals that inherit a mutated gene from both
parents have Homozygous FH (HoFH) (TFHF, 2015). HoFH is rare and estimated to affect 1 in
every one million people in the United States (Carlson, 2010, p. 8). HeFH, however, is much
more prevalent and is estimated to affect 1 in every 200 to 500 Americans (TFHF, 2015).
Individuals with FH can experience multiple complications from premature CVD. Early
diagnosis and treatment of FH provides individuals with better outcomes (Robinson, 2013).

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The purpose of this paper is to discuss the pathophysiology of familial

hypercholesterolemia (FH), current diagnostic criteria used for diagnosis of FH, the costeffectiveness of genetic testing for diagnosis, and the clinical management of FH.
Background
Men with untreated FH have a 50% chance of myocardial infarction prior to age 50
(TFHF, 2015). Women with untreated FH have an increased risk for MI before the age of 60
(National Human Genome Research Institute, 2013). Currently, only 10% of individuals living
with FH have been properly diagnosed (TFHF, 2015). Early and accurate diagnosis of FH is
essential to preventing the complications associated with this disease. The current guidelines for
cholesterol testing set forth by the U.S. Preventative Services Task Force does not recommend
testing prior to age 20 for men or women at risk for heart disease (U.S. Preventative Services
Task Force, 2008). Individuals at risk include those with strong family history of elevated
cholesterol levels and/or early myocardial infarctions (NHGRI, 2013). Testing is not
recommended for men younger than 35 who do not have risk factors for heart disease. There is
currently no recommendation for or against women who have no risk for heart disease to have
routine lipid screening (USPSTF, 2008). Current United States guidelines only recommend
screening for lipid disorders using serum lipid levels (USPSTF, 2008). Genetic testing in
addition to the recommended lipid panel would allow for early diagnose of FH. This would also
allow for earlier and improved management of FH, lowering the risk for complications from
CVD (Robinson, 2013).

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Methods
An electronic search was performed using the search engines Google Scholar and
CINAHL. The search criteria included articles published between 2010 and 2015. In Google
Scholar, the key words used were familial hypercholesterolemia and genetic testing. This search
yielded 1,080 articles. In CINAHL, the key word used was familial hypercholesterolemia. This
search yielded 40 articles. Articles were excluded due to the emphasis of outlaying subjects (i.e.
cardiovascular surgery, pregnancy). Fifteen articles were selected for this review based on
relevant content regarding familial hypercholesterolemia and genetic testing. The articles
selected included: one correlational study, one pilot study, one qualitative study, two literature
reviews, four quantitative studies, and six descriptive studies.
Review of the Literature
Familial hypercholesterolemia (FH) is a genetically linked disease known to cause an
alteration in the bodys ability to rid itself of cholesterol. The accumulation of the cholesterol
leads to premature cardiovascular disease (CVD). Many times the diagnosis of FH in not made
until after an individual suffers a complication from the premature CVD (Hopkins, Toth,
Ballantyne, & Rader, 2011, p. S9).
Diagnostic Criteria. Currently, there are many different criteria used to diagnosis FH.
The three most commonly used are the Dutch Criteria (Netherlands), the Simon Broome Criteria
(United Kingdom), and Make Early Diagnosis Prevent Early Deaths (United States of America)
(Fahed & Nemer, 2011, p. 6-7). The Simon Broome Criteria is the only criteria that requires the
presence of a genetic mutation for a definitive diagnosis of FH. The others use a combination of
LDL cholesterol levels, physical signs of high cholesterol, and family history (Fahed & Nemer,
2011, p. 7).

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Genetic Testing. Thirteen of the fifteen selected articles discussed the use of genetic
testing, different types available, and/or the feasibility of using genetic testing for diagnosis of
FH. The research showed that genetic testing has the ability to identify mutations causing FH
(Ned & Sijbrands, 2011). Several different types of genetic tests were reviewed in the research
and each were found to be feasible tools for the identification of mutations. However, there still
remains a diagnostic gap for the identification of every mutation causing FH (Fahed & Nemer,
2011, p. 8). There are over 100,000 identified LDLR mutations and current genetic testing can
only identify up to 80% of these mutations (Ned & Sijbrands, 2011). Newer genetic testing has
technology that will allow for increased sensitivity for mutation detection (Futema, et al., 2012,
p. 648). Genetic testing was found to be cost-effective for identification of mutations and
diagnosis of FH when followed up with cascade screening (Klose, Laufs, Marz, & Windler,
2014, p. 525). A decrease in the price of genetic testing would increase its use, allowing for
increased identification of FH (Talmud et al., 2013).
The interviews conducted by Will, Armstrong, & Marteau (2010) found that limited
knowledge regarding the use of genetic testing was a common deterrent among providers.
Although general practice providers were interested in genetic testing, they opted to refer
patients with suspected FH to a specialist due to their lack of knowledge. The interviews also
found providers agreed that patients and their families appear more compliant with the
management of FH (i.e. medications, lifestyle modification) after their disease was linked to a
genetic cause (Will, et al., 2010).
Cascade Screening. Cascade screening is a test that systematically screens family
members of patients diagnosed with FH (Ned & Sijbrands, 2011). The test can be performed on
first, second, and/or third degree relatives and uses low density lipoprotein cholesterol (LDL-C)

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levels or genetic analysis (Ned & Sijbrands, 2011). It was determined that the most cost-effective
approach for diagnosis of FH was to first perform genetic testing on the index patient to identify
the mutation. After the mutation is confirmed, relatives of the index patient undergo cascade
screening with the use of LDL-C levels (Klose, et al., 2014, p. 525). Cascade screening is a
simple process that was proven to reduce the average age at diagnosis of FH (Ned & Sijbrands,
2011). The use of cascade screening was found to be limited due to the lack of provider
knowledge and supportive structure for use in clinical practice (Muir, George, Laurie, Reid, &
Whitehead, 2010, p. 100).
Management of FH. Five of the fifteen selected articles discussed the management of
FH. The current recommended treatment goal set by the United States National Lipid
Association (NLA) and United Kingdom National Institute for Health and Care Excellence
(NICE) is to decrease LDL-C level by greater than 50%. If this is unattainable, the goal is reach
the maximum possible reduction in LDL-C level (Hovingh, Davidson, Kastelein, & OConnor,
2012, p. 967).
FH cannot be controlled through lifestyle modification alone (Klose, et al., 2014 p. 526).
Each of the five articles agreed the first line treatment for FH patients is a statin medication.
Statins were shown to reduce the risk for new onset coronary heart disease (CHD) by 80% in
patients with FH when compared to untreated patients (Ned & Sijbrands, 2011). Statin use also
showed a 37% reduction in death from CHD in patients with FH ages 20-79 (Ned & Sijbrands,
2011). Statins may need to be increased to the maximum approved dosage or to the highest
tolerated dosage for optimal effect. Statins can be combined with other LDL-C lowering
medications (i.e. Niacin, bile acid sequestrant, Ezetimibe, or stanol ester) to reach the maximum
reduction in LDL-C (Hovingh, et al., 2012, p. 967). The combination of statins with Ezetimibe

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showed a reduction in CVD risk when compared to placebo (Robinson, 2013, p. 143). The
addition of the bile acid sequestrant, Colesevelam, to statin/Ezetimibe combination therapy,
reduced the LDL-C level by an additional 12% (Robinson, 2013, p. 143). Klose et al. (2014) and
Hovingh, et al. (2012) discussed future pharmacological medications that are pending FDA
approval or in trial phase. Despite advances in pharmacological medications, the ultimate
treatment for FH will be gene replacement for mutations causing the disease (Hovingh, et al.,
2012, p. 970).
Discussion
The research showed the combination of genetic testing and cascade screening is a
feasible and cost-effective approach for the diagnosis of FH (Klose, et al., 2014, p. 525).
However, no evidence based research exists that identifies this approach as a standard of care for
diagnosis of FH. The UK Simon Broome criteria is the only guideline in use that requires a
positive genetic mutation for definitive diagnosis of FH (Fahed & Nemer, 2011, p. 7). Additional
research is needed to determine the best practice for diagnosis of FH.
Current treatments are not always effective in the management of FH and new treatments
are needed (Hovingh, et al., 2012, p. 970). There are limited studies available regarding the
management of FH (Klose, et al., 2014, p. 526). Data concerning pharmacological management
of FH patients is based on retrospective analysis and cohort comparisons (Klose, et al., 2014, p.
526). There are no evidence based treatments available at this time (Klose, et al., 2014, p. 526).
More research on the management of FH is warranted.
Implications
Implications for Nursing Education. Genetic testing combined with cascade screening
has been shown to be a practical and cost-effective diagnostic approach for FH (Klose, et al.,

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2014, p. 525). Advanced practice nurses in the primary care setting should be educated on the
pathophysiology, diagnosis, and management of FH. Increased knowledge about FH will allow
for more timely diagnosis and treatment. Earlier detection and management has been proven to
prevent heart disease and associated complications (Hopkins, et al., 2011, p. S9).
Implications for Nursing Practice. Advanced practice nurses in the primary care
setting can help to decrease the morbidity and mortality of individuals with FH. All primary care
providers are responsible for screening patients for FH (Hopkins, et al., 2011, p. S12).
Identifying patients at risk for FH can be accomplished during routine physical examinations
through the use of genetic testing in addition to physical findings and serum lipid panels.
Norsworthy et al. (2014) showed that diagnosing FH in the primary care setting is a practical
alternative to referring patients to lipid clinics and/or specialist. Increased access to genetic
testing and cascade screening in the primary care setting could help to decrease the portion of
undiagnosed patients with FH.
Implications for Future Research. The research showed a great need for more studies
in the area of genetic testing for diagnosis and management of FH. Although there are many new
technologies and medications on the horizon, there is a lack of standard diagnostic criteria
(Hovingh, et al., 2012, p. 965) and evidence based treatment for FH (Klose, et al., 2014, p. 526).
Research needs to be conducted to create an evidence based standard of care for the diagnosis
and management of FH patients.
Conclusion
Familial hypercholesterolemia is a genetic disease known to cause premature
cardiovascular disease. The literature reviewed showed the need for additional research to
establish a standard of care model for both the diagnosis and treatment of FH. The lack of

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evidence based research available delays the diagnosis and treatment of FH, increasing an
individuals risk for premature cardiovascular disease.

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