Reviewing Evidence on the Screening, Diagnosis, and Care of Familial Hypercholesterolemia

cholesterol buildup
Familial hypercholesterolemia is one of the most clinically relevant monogenic disorders contributing to the development of atherosclerotic cardiovascular disease.

Familial hypercholesterolemia (FH) is one of the most clinically relevant monogenic disorders contributing to the development of atherosclerotic cardiovascular disease (ASCVD). The prevalence of FH was estimated to be 1 in 200 to 1 in 250 individuals in studies in which genetic testing was conducted on large community population samples.1 However, the disease often remains undetected and thus untreated, with only 10% of individuals with FH receiving adequate diagnosis and treatment.2

Noting the recent accumulation of studies on FH, the authors of a Nature Reviews Cardiology article sought to summarize the key elements of a model of care for the condition that can be adapted as new evidence emerges.1 Selected points are highlighted below.

Screening and detection. A combination of  selective, opportunistic (eg, genetic screening of blood donors), systematic, and universal screening approaches is recommended to improve the detection of FH.Universal screening of children and child–parent (reverse) cascade testing is potentially a highly effective method for detecting patients with FH at a young age, before they develop ASCVD32… [and]… might be particularly relevant to communities with gene founder effects,” noted the review authors. “All children with FH should ideally be detected from the age of 5 years — or earlier if homozygous FH (hoFH) is suspected.”

Diagnosis. In the United States, elevated levels of low-density lipoprotein cholesterol (LDL-C) and a family history of FH are the main phenotypic criteria for FH diagnosis in children. Patients with hoFH, heterozygous FH (heFH), and polygenic hypercholesterolemia may also present with overlapping LDL-C levels, posing a challenge for the development of a standardized diagnostic tool for FH. 

Genetic testing. An international expert panel recently endorsed genetic testing in the care of patients with FH as it would “[allow] a definitive diagnosis, improve[e] risk stratification, address the increasing need for more potent therapies, improve[e] adherence to treatments, and increase[e] the precision and cost- effectiveness of cascade testing.”1,3 However, genetic testing remains underused due to issues such as cost, low access to genetic counseling, and lack of clinician knowledge in this area.

Clinical risk assessment. Cumulative lifetime exposure to elevated LDL-C is the key factor driving ASCVD risk in asymptomatic patients with FH, further underscoring the need for timely diagnosis and risk stratification. In addition to phenotypic and genetic factors, imaging of subclinical atherosclerosis, “might be the most useful clinical tool for assessing risk in FH.”1 For example, imaging of coronary artery calcium can be used to predict coronary events in asymptomatic middle-aged patients with FH taking statins, and computed tomography coronary angiography can be used to assess plaque burden and to intensify therapy.

Care of adults. Emerging evidence continues to support aggressive cholesterol-lowering therapy and lifestyle management in patients with FH “from as young as 8 years to maximally mitigate the cumulative cholesterol burden of risk.” The review authors emphasize the importance of patient-centered care and shared decision making, although health literacy is a challenge that may need to be addressed with some patients.

While there is insufficient evidence to develop strictly defined LDL-C treatment targets, current evidence-based recommendations stipulate that “in adult patients with FH, statin therapy and diet should initially be targeted to achieve a ≥50% reduction in LDL-cholesterol level… and an LDL-cholesterol level <1.8 mmol/l (70 mg/dl) or <2.6 mmol/l (100 mg/dl)… for primary prevention, and <1.4 mmol/l (55 mg/dl) or <1.8 mmol/l (70 mg/dl)… for secondary prevention or for patients at very high risk.”1

The addition of ezetimibe is indicated in patients who do not achieve the recommended LDL-C levels with statins alone. The use of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor as a third-line therapy is recommended in those patients or in patients who are intolerant to statins. The addition of a PCSK9 inhibitor in patients with heFH can further reduce LDL-C levels by approximately 60% and lead to recommended treatment targets in more than 80% of patients. However, these agents should not be used during pregnancy, as they cross the placenta and their impact on fetal development has not yet been determined.

Care of children. Extensive evidence supports the treatment of FH starting in childhood, as “[m]odest and sustained reductions in LDL- cholesterol levels from early life can have a major effect on reducing mortality associated with ASCVD.” Initial therapy is based on lifestyle management in early childhood, with the addition of statins by age 10 years in children with HeFH and upon diagnosis in children with hoFH. Ongoing research is investigating the efficacy and safety of PCSK9 inhibitors in children with heFH or hoFH.4,5

Radical therapies and novel approaches. Lipoprotein apheresis may be required in severe cases of FH, including in pregnant women, and “liver transplantation remains the only curative therapy for patients with severe hoFH.”

In ongoing studies, an array of novel treatment approaches are being examined, including functional LDL receptor gene transfer therapy in patients with hoFH and targeted RNA-based therapies to lower elevated lipoporotein(a) levels.6-8

Review authors also emphasized the importance of clinical registries, patient support groups and networks, and the need for structured research programs that are “underpinned by actionable dissemination and implementation strategies, research skills and training among service providers, and sustainable funding models.” They stated that a “major challenge is translating new evidence into health policy and routine care. Systems approaches for supporting health organizations and providers in addressing these gaps in care and service provision are essential.”

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We spoke with Seth Shay Martin, MD, MHS, associate professor of medicine at the Johns Hopkins University School of Medicine in Baltimore, Maryland, and director of the Advanced Lipid Disorders Program of the Ciccarone Center at Johns Hopkins.

Cardiology Advisor: What are examples of the latest advances in knowledge or practice pertaining to FH?  

Dr Martin: A big advance in practice has been the introduction of PCSK9 inhibitors. When added to statins and ezetimibe, this class of medications can lower LDL-C by 60% — sometimes the reduction can be lower, but in my experience the effect is commonly approximately 60%. This leads to patients coming back to clinic really satisfied.

Cardiology Advisor: What is the optimal approach for the treatment of these patients, and what are some of the top treatment challenges? 

Dr Martin: The optimal approach is to follow the 2018 American Heart Association/American College of Cardiology multi-society guidelines, which recommend a combination approach of lifestyle modification with first-line maximal statin therapy, followed by the addition of ezetimibe and PCSK9 inhibitors. The LDL-C threshold at which additional therapy should be considered is 70 mg/dL in high-risk patients with ASCVD and FH. In patients with isolated FH (termed severe hypercholesterolemia by the guidelines, based on LDL-C levels ≥190 mg/dL), the LDL-C threshold is 100 mg/dL.

Cardiology Advisor: What are other relevant treatment implications for clinicians who treat these patients?

Dr Martin: One of the joys in taking care of a patient with FH is taking care of a family. It is a genetic disorder with a 50% chance of being passed from parent to child. It is key to perform cascade testing to identify other members of the family; family visits to the clinic can be beneficial for all.

Cardiology Advisor: What are remaining needs in this area?  

Dr Martin: There is a great need for increasing awareness and diagnosis rates for FH. This is what our center is working to do as partners of the FH Foundation and as a CASCADE FH Registry site.


  1. Watts GF, Gidding SS, Mata P, et al. Familial hypercholesterolaemia: evolving knowledge for designing adaptive models of care [published online January 23, 2019.] Nat Rev Cardiol. doi:10.1038/s41569-019-0325-8
  2. Representatives of the Global Familial Hypercholesterolemia Community. Reducing the clinical and public health burden of familial hypercholesterolemia: a global call to action [published online January 2, 2020.] JAMA Cardiol. doi:10.1001/jamacardio.2019.5173
  3. Sturm AC, Knowles JW, Gidding SS, et al; Convened by the Familial Hypercholesterolemia Foundation. Clinical genetic testing for familial hypercholesterolemia: JACC scientific expert panel. J Am Coll Cardiol. 2018;72(6):662-680.
  4. Gaudet D, Langslet G, Gidding SS, et al. Efficacy, safety, and tolerability of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia: rationale and design of the HAUSER- RCT study. J Clin Lipidol. 2018;12(5):1199-1207.
  5. US National Library of Congress – Open label study to evaluate safety, tolerability and efficacy of evolocumab (AMG 145) in pediatric subjects (10 to 17 years of age) with heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH). (HAUSER-OLE) 2019. Accessed March 11, 2020.
  6. Ajufo E, Cuchel M. Recent developments in gene therapy for homozygous familial hypercholesterolemia. Curr Atheroscler Rep. 2016;18(5):22.
  7. Hegele RA, Tsimikas S. Lipid-lowering agents: targets beyond PCSK9. Circ Res. 2019;124(3):386-404.
  8. Tsimikas, S. RNA- targeted therapeutics for lipid disorders. Curr Opin Lipidol. 2018;29(6):459-466.

This article originally appeared on The Cardiology Advisor