Hiding in Plain Sight: Familial Hypercholesterolemia (FH)

Written By Ian Riddock

Case Presentation:

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

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. 




CardioAdvocate Checklist:

Blood tests (biomarkers):

Treatment Goals for FH:

  • Primary Prevention: FH with no ASCVD

    • > 50% LDL-C reduction, and

    • LDL-C < 100 mg/dL

  • Secondary Prevention: FH + ASCVD

    • > 50% LDL-C reduction

    • LDL-C < 70 mg/dL

  • Check ApoB 

    • May be used as the preferred biomarker for all patients with high TG, diabetes, obesity, metabolic syndrome or “very low LDL-C” for screening, diagnosis, risk management (Ia ESC/EAS) 

    • No fasting required. Let’s repeat that again – No fasting required

  • Check Lipid panel

    • LDL-C: primary biomarker due to availability, familiarity and legacy. Calculated metric. Usually not directly measured.

      • A surrogate for LDL particles

      • Friedewald equation no longer the preferred way to calculate LDL-C but remains most common

      • Hopkins-Martin or NIH are the preferred equations

        • If LDL-C not being calculated using above, ask your lab to change

      • Less accurate if TGs > 150 mg/dL

      • The higher the TGs, the worse LDL-C performs (discordance)

      • The more LDL-C is lowered (< 70 mg/dL), the less accurately it reflects LDL particles and ApoB

    • NonHDL-C (Total Cholesterol minus HDL-C): as good or better than LDL-C

      • Recommended over LDL-C when TG high (> 150 mg/dL) 

        • Despite this ancient guideline recommendation (ca. 2001), it is seldom followed in clinical practice

      • Reflects LDL-C + other atherogenic cholesterol, mainly VLDL-C

      • Despite recommendations, many labs don’t list Non-HDL-C in report

        • If not listed, can be manually calculated (TC - HDL-C), but nobody likes to do math in a busy clinic

        • If your lab doesn’t list NonHDL-C, request that they do - it’s not hard

        • Comes “free” in standard Lipid panel - but this isn’t helpful if the lab doesn’t list it, or the provider doesn’t calculate it or know what it means

      • No fasting required. Let’s repeat that again – No fasting required

        • So why do we continue to use LDL-C? Great question. Mostly because it’s cheap, available, standardized (?), and let’s face it - would probably cause mass hysteria if we replaced it overnight. It works pretty good. But we do have better tools. Only YOU can advocate for better.

    • HDL-C: Never has been a target or goal of therapy in any cholesterol guideline

      • HDL-C tells us nothing about the functionality of HDL particles. For example:

        • High HDL-C can be seen with dysfunctional HDL, where HDL cannot offload cholesterol and hence the concentration (mg/dL) goes up

        • Conversely, low HDL-C has been seen with highly efficient HDL, where HDL is so efficient at offloading cholesterol that the concentration is low. 

          • Apo A-1 Milano. Founder effect genetic variant with very low HDL-C and associated with higher lifespan

      • Until an HDL functional assay is developed, HDL-C or HDL-P will not be particularly helpful in lipid management

      • Stop saying “good cholesterol”. It’s misleading and dangerous.

      • Years (decades) of poor public health messaging on this topic has set us back. We’re trying to undo this.

      • Giving out “points” for high HDL-C may underestimate risk

        • Women typically have high HDL-C than men - another example of missing the mark in assessing CV risk in women

      • *Caveat: There may be value in seeing a low HDL-C on a lipid panel - it may alert the clinician to a problem - particularly the “atherogenic triad.” But only if they are trained to look at TG and then observe or calculate the nonHDL-C discrepancy to LDL-C

    • Triglycerides (TGs): Not themselves known to be directly causal to atherosclerosis, though this continues to be investigated

      • If > 500 mg/dL (severe) the primary objective is to treat the TGs to avoid the risk of pancreatitis

      • Pancreatitis is much more likely with TG > 1000 mg/dL, but since TGs fluctuate considerably, a fasting level > 500 mg/dL is severe and warrants urgent attention

      • If 150-499 mg/dL, look for and address associated comorbidities (DM and dysglycemia, obesity and visceral adiposity, metabolic syndrome, fatty liver disease)

        • “Atherogenic triad”: High TG’s, low HDL-C, high sdLDL-P

        • Should alert you to the high likelihood of elevated ApoB and discordance to LDL-C (lower LDL-C may be misleading)

          • Underestimates risk

    • TC/HDL-C Ratios: Just as dumb and dangerous as above

      • Focus on LDL-C, nonHDL-C and ApoB. That’s all you really need

        • In fact, if you just focused on ApoB, you’d be doing great

    • LDL-P: Should reflect and be concordant with ApoB. 

      • In general, can be used in place on ApoB to account for discordance or inaccuracies with LDL-C (residual risk) 

      • In our experience, LDL-P is not as well standardized as ApoB. We have observed not too infrequent cases of discordance between ApoB and LDL-P. 

      • ApoB is preferred over LDL-P

      • ApoB/LDL-P discordance is a much more advanced and nuanced discussion with many gaps in knowledge. Use clinical judgment.

        • If ApoB > LDL-P, treat ApoB

        • If LDL-P > ApoB

          • Look for other cardiometabolic comorbidities (DM and dysglycemia, high TG, fatty liver, obesity) and treat

            • It may be prudent to consider more aggressive treatment of LDL-P

        • If no other cardiometabolic features present, consider LDL-P a false positive

    • Small dense LDL-P vs Large buoyant LDL-P (Hint: they’re all bad)

      • “Size Doesn’t Matter” - when it comes to LDL particles. They are all atherogenic.

      • No convincing data exists demonstrating increased atherogenicity to small dense LDL-P, once total LDL-particle number is accounted for

      • Measuring sub-particle fractions does not appear to provide additional clinical value apart from measuring ApoB, or total LDL-particle count

      • *Caveat - there may be some value in measuring advanced lipid subfractions in the individual with insulin resistance who has the “Pattern B” (old nomenclature for sdLDL-P) phenotype and is transitioning to a “Pattern A” (large buoyant LDL-P) through optimal treatment pathways and therefore providing some bit of “proof” of progress. 


Primary Prevention at Very High Risk (IIa ESC/EAS)

  • ≥ 50% LDL-C reduction and 

  • LDL-C < 55 mg/dL

Secondary Prevention at Very High Risk (IIa ESC/EAS)

  • ≥ 50% LDL-C reduction and

  • LDL-C < 55 mg/dL

Primary Prevention without additional high risk features - i.e. “Severe primary hypercholesterolemia” with LDL-C ≥ 190 mg/dL (2018 ACC/AHA)

  • “High intensity statin” regardless of 10 year risk calculation

    • Aimed at > 50% LDL-C reduction

  • If LDL-C remains > 100 mg/dL, add ezetimibe

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)

    • ANGPTL3 inhibitor

Other Therapies:

  • LDL Apheresis


Deep Dive

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 Biomarkers

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).

Ian Riddock
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