Familial Hypercholesterolemia: Our Call to Action

Familial hypercholesterolemia (FH), an autosomal dominant condition involving markedly elevated low-density lipoprotein cholesterol (LDL-C), was first described more than a century ago, but is still a highly under-recognized and underappreciated condition, present in an estimated 1 in 200 to 500 individuals (or higher in certain founder populations) in the heterozygous form (genetic defect inherited from one parent), and 1 in 1 million in the homozygous form (genetic defects from both parents), making FH one of the most common of serious genetic disorders. FH is more common than other diseases often receiving much greater attention, such as multiple sclerosis, cystic fibrosis, and AIDS. Total cholesterol concentrations in those with heterozygous FH (HeFH) typically range from 350-500 mg/dL and in homozygous FH (HoFH) from 600 to 1000 mg/dL. If not identified and treated at an early age, FH can result in a 20-fold or greater increased lifetime risk of coronary heart disease compared to the general population, translating to a 50% risk of a fatal or nonfatal coronary event by age 50 in a man or 30% risk by age 60 in a woman.^1-3 There are an estimated 620,000 children and adults with FH in the United States; it is estimated that less than 10% have been diagnosed because of gaps in screening, recognition, and classification.^1,2 Noteworthy is that the Centers for Disease Control and Prevention recognizes FH as a Tier 1 genetic disorder, indicating that sufficient evidence for health benefit exists to implement case finding via family history-based screening, cascade screening, or other strategies.³

In this issue of Circulation, Gidding et al³ have provided an extensive agenda to improve upon efforts to identify and manage this important condition, including reviewing the pathophysiology and suggestions for updating diagnostic criteria, screening, treatment options, and suggested models of care.

While there have been a number of proposed criteria for diagnosing FH1, the complexity of some has perhaps been a hindrance in identifying many with the condition. In the new AHA scientific statement on FH3, Gidding et al have proposed a much simpler clinical criteria, which if widely implemented in a systematic fashion, could efficiently identify many with this condition:

1. Heterozygous FH (HeFH): LDL-C > 160 mg/dL (4 mmol/L) for children and >190 mg/dL (5 mmol/L) for adults and with one first degree relative similarly affected or with positive genetic testing for an LDL-C raising gene defect (LDL receptor, apolipoprotein-B (apo B) or proprotein convertase subtilisin/kexin type 9 (PCSK9))
2. Homozygous FH (HoFH): LDL-C > 400 mg/dL (10 mmol/L) and one or both parents

1. having clinically diagnosed FH,
2. positive genetic testing for an LDL-C raising ( LDL receptor, apo B or PCSK9) gene defect, or
3. autosomal recessive FH If LDL-C > 560 mg/dL (14 mmol/L) or LDL-C > 400 mg/dL (10 mmol/L) with
4. aortic valve disease or
5. xanthomata at less than 20 years of age, homozygous FH highly likely.

In addition, as a genetic etiology related to LDL receptor function is present in most people with FH, the statement provides alternative clinical criteria for when genetic testing is also performed.

The AHA statement additionally points to the need for cascade screening after identification of index cases to identify all affected family members and such an approach can be efficient at identifying many with FH in general. Also noted is the value of a multidisciplinary care team including physicians, nurses, genetic counselors, pharmacists, and dietitians and the need for centralized models of care for FH to increase awareness and recognition. Finally, important issues regarding patient perspectives such as risk perception and the fear of experiencing cardiovascular events, implications of genetic diagnoses, lifestyle behaviors, quality of life issues, medication side effects and adherence, and costs of treatment all need to be considered and are an important part of the statement. Also reiterated by others including the FH Foundation and the National Lipid Association is the need for ICD-10 codes for HoFH, HeFH, and a family history of FH, which will allow patients “insurance rights” that other inherited diseases have. Without such diagnoses codes to flag such patients once identified, progress in their treatment is often hampered.

Much excitement in the field has been generated in recent years due to the availability of newer treatment options. Since the availability of LDL-apheresis and statins over the past few decades, patients with FH have been able to live much longer lives. While high intensity statin treatment remains the mainstay for most with FH, many will still need additional treatment for further LDL-C lowering, including those unable to tolerate statin therapy, or where suboptimal therapeutic response is obtained. Indicated for HoFH only, mipomersen, an antisense inhibitor of apo-B synthesis can reduce LDL-C by an additional 25% over other maximal drug therapy and lomitapide, an oral inhibitor of microsomal transfer protein can lower LDL-C by 50%.³ Most recently approved by the FDA this summer is PCSK9 monoclonal antibody treatment (alirocumab and evolocumab are currently available with others in development) indicated for those with atherosclerotic cardiovascular disease (ASCVD) or HeFH who need further LDL-C lowering beyond other therapy; these agents provide (beyond statins) approximately 50-60% LDL-C lowering in HeFH, and evolocumab also indicated for HoFH provided approximately 30% LDL-C lowering in such patients, except those null for LDL receptors. Short-term outcome data are promising for added ASCVD risk reduction beyond standard of care therapy. Longer-term cardiovascular event trials with PCSK9 inhibitors are underway to demonstrate whether such treatment beyond statins translates into cardiovascular benefit.⁴ All of these newer therapies offer significant hope beyond what statins and other therapies can provide for combating the previously often inevitable and early cardiovascular morbidity and mortality associated with FH.

The AHA, in collaboration with the FH Foundation (www.fh-foundation.org), other relevant societal partners (e.g., National Lipid Association, American College of Cardiology, American Society for Preventive Cardiology, and Preventive Cardiology Nurses Association), as well as industry partners, needs to make FH an important priority in their missions, promoting educational and awareness efforts directed both at the healthcare and lay community. With the AHA clearly being the platform the public recognizes as the key authoritative source of information on cardiovascular diseases, and like with other highly successful campaigns such as Go Red for Women™ (which involve dedicated groups of community members organizing highly successful benefits for the cause), a similar effort around FH is a key strategy that would resonate well with AHA’s mission to “build healthier lives free of cardiovascular diseases and stroke” and the goals to improve cardiovascular health and reduce deaths from cardiovascular diseases and stroke by 20% by the year 2020. The AHA is uniquely positioned as the leader in advocacy efforts in cardiovascular health and with the greatest ability to educate and empower the community to make FH an important “call to action” priority.