In the JournalsPerspective

Familial hypercholesterolemia underdiagnosed, undertreated worldwide

Between 14 million and 34 million people have familial hypercholesterolemia worldwide, but less than 1% of cases are diagnosed in most countries, according to a consensus statement from the European Atherosclerosis Society.

A consensus panel from the society recommended increased screening for familial hypercholesterolemia, which it said could lead to better prevention of CHD.

Børge G. Nordestgaard, MD, DMSc, of Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, and colleagues wrote that although previous research had estimated that 1 in 500 white people have familial hypercholesterolemia, a recent Danish screening project found the prevalence in that population was 1 in 200. Based on extrapolations from those ratios, the panel estimated the worldwide prevalence of familial hypercholesterolemia is 14 million to 34 million people.

The panel wrote that previous research found that most individuals with familial hypercholesterolemia fail to meet recommended LDL cholesterol targets, and they may face as much as a 13-fold increased risk for CHD compared with those who do not have familial hypercholesterolemia.

“Owing to severe underdiagnosis and undertreatment of [familial hypercholesterolemia], there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition,” the panel wrote.

Of the 22 countries for which data are available, 12, including the United States, have a diagnosis rate of 1% or less, according to the consensus statement, which estimates that for most countries for which data were not available, the diagnosis rate is less than 1%.

The panel recommended familial hypercholesterolemia screening for individuals who have a family member who:

  • Presents with familial hypercholesterolemia.
  • Is an adult with a plasma control level ≥8 mmol/L (≥310 mg/dL) or a child with a plasma control level ≥6 mmol/L (≥230 mg/dL).
  • Has premature CHD.
  • Has tendon xanthomas.
  • Had sudden premature cardiac death.

The panel wrote that for those with familial hypercholesterolemia, LDL cholesterol targets are <3.5 mmol/L (<135 mg/dL) for children, <2.5 mmol/L (<100 mg/dL) for adults, and <1.8 mmol/L (<70 mg/dL) for adults with known CHD or diabetes.

The panel recommended that everyone with familial hypercholesterolemia and their families receive counseling on diet, physical activity and smoking cessation. It recommended adults be prescribed statins immediately upon diagnosis, and children with familial hypercholesterolemia be considered for statin therapy starting at age 8 to 10 years. Other pharmacotherapy options recommended for all individuals in case statins are insufficient include ezetimbe and bile acid-binding resin. The panel also recommended lipoprotein apheresis in children with two copies of the gene for familial hypercholesterolemia, in adults with two copies of the gene for familial hypercholesterolemia, and in adults with one copy of the gene for familial hypercholesterolemia and treatment-resistant CHD.

Disclosure: The panel’s work was supported by grants to the European Atherosclerosis Society from Amgen, Aegerion, AstraZeneca, Genzyme, Hoffman-La Roche, Kowa Europe, Novartis and Sanofi-Aventis/Regeneron. See the full statement for a list of the panel members’ relevant financial disclosures.

Joshua W. Knowles MD, PhD, FAHA, FACC

Joshua W. Knowles

  • I am very supportive of the overall message of the European Atherosclerosis Society (EAS) guidelines. The recommendations are quite sound. 

    The exact figure for prevalence of familial hypercholesterolemia in the United States is unknown. There is no distinct ICD-9 code for familial hypercholesterolemia and very little population-based data from the US to answer that question. We know that familial hypercholesterolemia is at least as common as 1 in 500 and affects all race/ethnic groups. There is emerging data that familial hypercholesterolemia is actually more common than that (perhaps as common as 1 in 200). So there are at least 600,000 patients in the US with familial hypercholesterolemia and maybe more than double that. The commonly quoted figure is that less than 10% of familial hypercholesterolemia patients are diagnosed in the US. However, it is possible that as little as 1% to 2% are diagnosed with familial hypercholesterolemia (this latter number is cited in the EAS document, but the data to support that number are not very concrete).

    Many people with familial hypercholesterolemia have been diagnosed with "high cholesterol."  However, because of lifelong exposure to high LDL levels, familial hypercholesterolemia patients are at substantially elevated risk and require more aggressive lipid lowering than patients with "garden variety" high cholesterol. In addition, because familial hypercholesterolemia is an autosomal dominant disease and passed in families, once a patient with familial hypercholesterolemia is diagnosed, it is recommended that all family members are screened for familial hypercholesterolemia. This is referred to as "cascade" screening. Distinguishing a patient with familial hypercholesterolemia (vs. "garden variety" high cholesterol) is absolutely essential.

    In terms of treatment, it is absolutely clear both from US and European data that familial hypercholesterolemia patients are routinely undertreated. In fact, the majority of familial hypercholesterolemia patients do not achieve ideal LDL levels (<100 mg/dL). 

    I am the Chief Medical Officer for the Familial Hypercholesterolemia Foundation (the FHF), a patient-founded, patient-led, nonprofit organization with the goal of raising awareness and improving the treatment of familial hypercholesterolemia patients. At the FHF, one of our major initiatives is the establishment of a national patient registry for familial hypercholesterolemia, which will be launched in September. Hopefully, getting current, real-world data on prevalence and treatment of familial hypercholesterolemia will help answer many of these questions. 

    We already know that familial hypercholesterolemia places a huge burden on the health care system. There is a 20-fold increased lifetime risk for MI. Untreated men with familial hypercholesterolemia have a 50% chance of cardiac event before age 50 and untreated women have a 30% chance by age 60. Familial hypercholesterolemia accounts for a sizable proportion of very early-onset cardiac events (20% of MIs before age 45). Besides the devastating consequences to the patients, this is a hugely expensive problem for our health care system. The good news is that things do not have to be this way. Familial hypercholesterolemia is relatively easy to diagnose based on lipid levels, family and personal medical history, and physical exam. And generic statin-based regimens are highly efficacious. So we view familial hypercholesterolemia as a "winnable battle." The CDC does too, and has classified cascade screening for familial hypercholesterolemia as a Tier 1 condition. The Dutch and UK approaches have both shown that screening for familial hypercholesterolemia is highly cost-effective (see the NICE guidelines from the UK).

    We are starting to see a groundswell of momentum for familial hypercholesterolemia over the last few months due to a combination of thoughtful leadership from organizations like the EAS, AHA, National Lipid Association (NLA) and patient organizations like the FHF. There are multiple new therapies for familial hypercholesterolemia that have recently been approved or are in clinical trials. In addition to the EAS statement, the NLA published guidelines a few years ago and the AHA is planning a scientific statement on familial hypercholesterolemia. The most important recommendations of the document center on the public health aspects of familial hypercholesterolemia and the need for cascade screening once an index case has been identified. Also important is the aggressive targets for lipid lowering and the emphasis on lifetime risk for CVD in familial hypercholesterolemia patients. What is really needed is to get the message out to the public and healthcare providers. 

    • Joshua W. Knowles, MD, PhD, FAHA, FACC
    • Instructor, Cardiovascular Medicine, Stanford University, Palo Alto, Calif.
      Attending Physician, Stanford Center for Inherited Cardiovascular Disease, Familial Hypercholesterolemia (FH) Clinic, Palo Alto, Calif.
      Chief Medical Officer, the FH Foundation, South Pasadena, Calif.
  • Disclosures: Knowles reports no relevant financial disclosures.