Hiding in Plain Sight
Patient A:
Heart attack by age 9? Bypass by age 12? LDL-C 780 mg/dL! How on Earth does that happen? Having extremely high levels of LDL-C (> 400 mg/dL) since birth, that’s how. Familial hypercholesterolemia (FH) results from a genetic defect which impairs the ability of LDL receptors (LDLR) on liver cells from clearing ApoB containing atherogenic particles (LDL, VLDL, Lp(a)) from the blood. This results in severely elevated circulating levels of these particles in the bloodstream, which is manifested by extremely high levels of LDL-C in a lipid panel.
Patient B:
A 42 year old woman presents to the lipid clinic with LDL-C ~ 250 mg/dL. She proclaims: “I’ve been told I have really high cholesterol since I was in highschool, when they did a health screening. They told me I needed to change my diet and lose weight. I’m a professional dancer and have been eating healthy ever since and nothing seems to change my cholesterol numbers”.
Physical exam revealed tendon xanthomas of the hands (Xanthoma, tendon - Dermatology Advisor) and corneal arcus of the eyes (Correlating corneal arcus with atherosclerosis in familial hypercholesterolemia - PMC, (Arcus Senilis - EyeWiki).
She was referred for genetic testing (often helpful for insurance coverage of advanced lipid therapies) through Ambry Genetics, which confirmed Heterozygous Familial Hypercholesterolemia (HeFH). The news of this genetic condition was emotionally overwhelming for this particular patient, who unfortunately and needlessly, lived her adolescent and adult life feeling her “lack of dietary control and exercise intensity” were to blame for her cholesterol condition.
The above cases are examples of the 2 types of Familial Hypercholesterolemia:
Homozygous (HoFH):
- LDL-C > 500 mg/dL
- 1 in 300,000
- 100% chance of passing along the gene
Heterozygous (HeFH):
- LDL-C - 1 in 200-300
- LDL-C ≥ 190 mg/dL or nonHDL-C > 220 mg/dL in adults
- ≥ 160 mg/dL or nonHDL-C > 190 mg/dL in children/adolescents (and some young adults in 20s)
- Autosomal Dominant (50/50 chance of passing the disease along)
- Due to genetic defect in LDLR (most common), ApoB (less common) or PCSK9 gain of function (rare)
Flying Under the Radar
Why do these cases go undertreated?
Is your (or a family member’s) LDL-C ≥ 190 mg/dL (adult) or ≥ 160 mg/dL (children)?
If so, this should raise suspicion for FH and warrants further evaluation to rule this out.
While rare, undiagnosed and untreated patients with HoFH are all but guaranteed a future of recurrent ASCVD events beginning in the pediatric age range.
Much more common however, patients with undiagnosed and untreated HeFH have a 25X higher lifetime risk of having an ASCVD event! 25 times higher!
And it’s easy to screen for and detect!
So with such extremely high cholesterol from birth, how do these patients hide from us? I mean, aren’t doctors checking cholesterol levels all the time?
No, sadly they are not. Lipids are frequently not checked in children. Often not in adults either - even when they get admitted to the hospital for a heart attack! Crazy isn’t it? But it's true.
It’s not uncommon for patients to proclaim “But I just went to the lab and they took a ton of blood from me. Wasn’t my cholesterol checked then?” No, it may not have been.
A checklist of targeted recommendations based on published guidelines
Blood tests (biomarkers):
- Check Lipid Panel: See What's Your ApoB? A Practical Approach to Lipid Management
- LDL-C > 190 mg/dL or nonHDL-C > 220 mg/dL in adults
- > 160 mg/dL or nonHDL-C > 190 mg/dL in children/adolescents (and some young adults in 20s)
- Refer to Lipid specialist
- Look in the mirror
- Examine your eyes to assess for presence of
- Examine/feel the backs of your hands and achilles or on the elbows and knees, to assess for tendon xanthomas as seen in this paper: Cutaneous Manifestations in Homozygous Familial Hypercholesterolemia
- Use FH calculator
- Genetic Testing
- Many companies offer testing at low cost to patient, some for free
- Check Lp(a)
- If elevated (> 125 nmol/L), and FH present, represent “Double Whammy” with severely elevated combined risk of ASCVD event
- Consider Coronary Artery Calcium Screening (CAC)
- May impact aggressiveness of therapy to achieve target LDL-C
Treatment Goals for FH:
- Primary Prevention: FH with no ASCVD
- > 50% LDL-C reduction, and
- LDL-C
Primary Prevention at Very High Risk (IIa ESC/EAS)
- ≥ 50% LDL-C reduction and
- LDL-C
Drug Therapy:
- Very High Risk
- Statins
- Combo with Ezetimibe if statins not sufficient
- Combo with PCSK9i if not at goals despite max statin + ezetimibe
- simRNA (small interfering ribonucleic acid)
- Leqvio (inclisiran)
- ANGPTL3 inhibitor
- EVKEEZA.com
- Approved for HoFH
Other Therapies:
- LDL Apheresis
Going into detail on the evidence behind the recommendations and history of treatment for this phenotype.
FH Awareness
FH is already underrecognized and undertreated. Pharmacotherapy is indicated for those with LDL-C > 190 mg/dL and may be considered for those with LDL-C 160-189 mg/dL, according to all reputable lipid guidelines.
According to a recent NHANES (National Health and Nutrition Examination Survey) report, 2.1% of the US population has an LDL-C > 190 mg/dL, yet more than 1/4 of them (26.8%) were unaware of it or were not on any treatment. This represented 1.4 million Americans. “Being unaware and untreated was more common in younger adults, men, racial and ethnic minority groups, those with lower education attainment, those with lower socioeconomic status and those without health insurance.” (Prevalence, Awareness, and Treatment of Elevated LDL Cholesterol in US Adults, 1999-2020 | Cardiology). Another example of healthcare disparities, to which more awareness campaigns, like ours, hope to improve.
Efforts to combat this lack of awareness has prompted The National Lipid Association and others to advocate CMS to make LDL-C a “Quality Measure,” (Quality Measures | CMS) a tool that CMS uses to financially incentivize healthcare systems and providers to adhere to the best evidence based medicine.
Lack of Screening and Guideline Controversy
It doesn’t help when organizations such as the USPSTF recently published an updated guideline claiming there is not sufficient evidence at this time to support routine lipid screening in the pediatric population (Screening for Lipid Disorders in Children and Adolescents: US Preventive Services Task Force Recommendation Statement | Cardiology | JAMA).
The NLA and ASPC issued a joint letter to the USPSTF strongly condemning this action, stating:
“This statement was unnecessary and potentially harmful to the population. USPSTF standards require an unreasonable level of evidence to demonstrate the obvious, which is that identification of a common inherited condition with population screening will enable early treatment and prevention of serious outcomes decades later and is superior to the alternative of hopeful screening of adults who already have advanced disease from the untreated condition.”(NLA/ASPC response to the USPSTF recommendation statement on screening lipid panel in children and adolescents - Journal of Clinical Lipidology).
The joint letter further argues the efficacy and safety of treating children with FH in a placebo controlled statin trial (Efficacy and Safety of Statin Therapy in Children With Familial Hypercholesterolemia: A Randomized Controlled Trial | Cardiology | JAMA) and in a large study by Dr. John Kastelein (Efficacy of statins in familial hypercholesterolaemia: a long term cohort study | The BMJ) using registry data from the Netherlands, where screening is universal and covered. Long term data from this study (20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia | NEJM) has now demonstrated that identifying and treating the offspring of FH patients earlier in life resulted in significant delay in the onset of cardiovascular events such as heart attack.
The absurdity of the USPSTF recommendations obligates a young child to a shorter lifespan that is spent battling recurrent and otherwise preventable morbidity in the form of devastating ASCVD events.
Lack of Inertia for Earlier Detection, Prevention and Treatment
Evidence supports that the earlier you identify and treat FH and early atherosclerosis, the more likely we are to prevent disease. (Determinants of Progression and Regression of Subclinical Atherosclerosis Over 6 Years | Journal of the American College of Cardiology).
Lack of Provider Knowledge
Many primary care providers are unfamiliar with FH and unfamiliar with when to screen for lipid disorders.
Even when parents request screening for LDL-C and Lp(a) for their children, many providers inform patients it’s “too early”.
Even worse, many providers continue to rely on archaic and erroneous notions around “cholesterol ratios”. See What's Your ApoB? A Practical Approach to Lipid Management
Patients still report the following scenario after finally seeking out a lipid specialist: “I’ve always been told that although my LDL-C is really high, but so is my HDL-C, which makes my ratio ok and I don’t need any treatment.”
Misinformation
Social media and other internet sources are unfortunately littered with misinformation about the causality of LDL with ASCVD.
These “LDL Deniers”, as some have referred to them, tend to have a strong passion for a “ketogenic lifestyle” and in defending the purported health benefits of such a lifestyle have dangerously made it their mission to “debunk” the causality of LDL to ASCVD. They fail to understand risk - both near term and lifetime. See The Straw That Breaks the Camel's BacK - LMHR (Lean Mass Hyper Responder).