Familial Hypercholesterolemia (FH) Is Not Detected by Measuring Cholesterol

Elevated blood cholesterol is a common reason why people see their doctor. Most of us have been told that high cholesterol increases the risk of cardiovascular disease, and we are usually urged to lower it by any means available. But, the problem is that high cholesterol is often harmless, and heart disease can occur in the absence of high blood cholesterol.

Familial Hypercholesterolemia (FH) is Not Detected by Measuring Cholesterol

However, there is a genetic disorder called familial hypercholesterolemia (FH) that is associated with high blood cholesterol and increased risk of suffering from coronary artery disease (CAD) early in life.

Severe hypercholesterolemia is defined as having an LDL cholesterol (LDL-C) >190 mg/dL (4.9 mmol/L). FH is one of the underlying causes of severe hypercholesterolemia. FH is an autosomal dominant, genetic disorder where the clearance of LDL particles by liver cells is impaired, leading to high blood levels of LDL-C.

The liver is the gatekeeper for LDL and is responsible for its clearance. Liver cells express LDL-receptors on their surface, that bind LDL and remove it from the blood stream. FH results from defects in the hepatic uptake and degradation of LDL via the LDL-receptor pathway.


It is often assumed that people with LDL-C >190 mg/dL (4.9 mmol/L) have FH and should, therefore, be treated aggressively with cholesterol-lowering drugs. But this is incorrect because most individulas with severe hypercholesterolemia don’t have FH.

So, what is the real prevalence of genetic mutations causing FH among patients with severe hypercholesterolemia? This is an important question because people with severe hypercholesterolemia do not necessarily have FH and are therefore at a relatively low risk of CAD compared to those with FH.

The issue was addressed recently in a very important paper by Amit V. Khera (Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts andBroad Institute, Cambridge, Massachusetts) and coworkers published in the Journal of the American College of Cardiology (JACC) (1).

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The objectives of Khera’s paper were twofold. The first was to assess the prevalence of FH mutations among people with severe hypercholesterolemia defined as LDL-C >190 mg/dL (4.9 mmol/L). The second was to address the question whether those with a gene mutation are at higher risk of CAD than those without the mutation, despite similar levels of LDL-C.

Three genes causative for FH were sequenced in 26.025 participants from seven previously described case-control studies and 11.908 patients from five prospective cohort studies. Some of these individuals had documented CAD and some had not. A control group with low LDL-C (< 130 mg/dL (3.4 mmol/L)) was also defined.

The results of the study were the following:

  1. Among approximately 40 thousand participants free from coronary artery disease, 6.7% had severe hypercholesterolemia defined as LDL-C > 190 mg/dL (4.9 mmol/L).
  2. Only 1.7% of those with documented severe hypercholesterolemia carried an FH mutation.
  3. At any LDL-C level, the risk of CAD was higher among FH mutation carriers than non-carriers.
  4. Compared with the reference group with LDL-C < 130 mg/dL (3.4 mmol/L) and no mutation, those with an LDL-C > 190 mg/dL (4.9 mmol/L) and no mutation had a sixfold higher risk of CAD while those with both and LDL-C > 190 mg/dL and an FH mutation had a 22-fold increase risk of CAD.
  5. An analysis of participants with serial lipid measurements over many years revealed that FH mutation carriers had higher cumulative exposure to LDL-C as compared with no carriers. This may be described as a more persistent hypercholesterolemia.

The study confirms that FH, as defined by gene sequencing is a rare disorder, even among patients with severe hypercholesterolemia (< 2%). However, when present, it carries a substantially increased risk of CAD.

It is evident that FH mutations explain only a small fraction of severe hypercholesterolemia in the population. So, a remaining question is what explains elevated LDL-C among the majority of people with severe hypercholesterolemia. Two possibilities highlighted by the authors of the paper are polygenic hypercholesterolemia and lifestyle factors, or a combination of these two. Of course, future genetic studies might find additional causal variants, genes not considered in this particular study.

The authors believe their data support the hypothesis that an FH mutation present since birth, increases CAD risk via lifelong exposure to LDL-C. By contrast, an elevation of LDL-C in those without a genetic mutation might reflect a time-limited exposure, partly related to lifestyle factors.

However, the authors don’t address the possibility that the increased risk of CAD associated with the FH gene mutation may be mediated by other factors than LDL-C.

Interestingly, FH mutations were found at all levels of LDL-cholesterol. Of all the 164 mutation carriers in the study, 44 (27%) had an LDL-C of < 130 mg/dL. Hence, the FH gene mutation may be present in individuals who don’t have hypercholesterolemia.

Practical Implications

The paper by Khera and coworkers confirms the malignancy of the FH gene mutation. Although the incidence is low, the implications are high. Therefore, genetic testing should be warranted to identify the disorder.

But who should have genetic testing? The cholesterol level does not seem to be helpful as the genetic mutation for FH is found in patients with both low and high LDL-C. However, the greatest risk associated with the genetic mutation is present in those who have LDL-C >190 in addition to the mutation. Therefore, genetic testing is probably only appropriate if severe hypercholesterolemia is present.

The 2013 ACC/AHA guidelines for primary prevention of cardiovascular disease suggest statin treatment for individuals with severe hypercholesterolemia (LDL-C >190 mg/dL (4.9 mmol/L)) (2). Obviously, those with a combination of severe hypercholesterolemia and the FH gene mutation will benefit most from such therapy. The question is whether statin treatment should be reserved for this group only.

If lifelong exposure to cholesterol is a critical issue, and fluctuations in LDL-C among those without the FH gene mutation explain the difference in risk between those with and without the mutation, lifestyle modification may be the most appropriate treatment for 98% of people with severe hypercholesterolemia.



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Archie Robertson
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Archie Robertson

Isn’t it obvious?
“Hence, FH may be present in individuals who don’t have hypercholesterolemia.”
The FH gene has nothing to do with familial hypercholesterolemia. In logic, this is called a black swan.

Mie
Guest
Mie

Nope. There is a large variety of mutations & consequently not everyone who has such a mutation has hypercholesterolemia.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC161432/

This doesn’t, of course, mean that FH isn’t genetic in origin.

js290
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js290

“High cholesterol is bad”… which is the observation and which is the concept? Observation vs Concept https://bit.ly/1lM3PFS

tannngl
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tannngl

This is kind of astounding. My son-in-law died at 34 of LAD total occlusion. My daughter had 3 children all still in diapers. First thing I wanted to do after taking care of them financially, was get the kids checked for FH. I had retired from a hospitla that specialized in coronary disease with interventional treatment andI knew this was the right thing to do, although kind of unusual with kids then. It was 2002. Kids had lipid profiles and both girls had high lipid panels. The little boy was normal. Not sure now what noral is for a kid…… Read more »

Axel F Sigurdsson
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Axel F Sigurdsson

Sorry to hear about this family history.
The combination of hypercholesterolemia and family history of premature coronary artery disease should always make one suspect FH. Genetic testing for this disorder has become more common in in recent years but i guess it’s still not widely available. https://heartuk.org.uk/fh-familial-hypercholesterolemia/genetic-testing-for-familial-hypercholesterolaemia-fh

tannngl
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tannngl

Thanks so much for the link. I’ll have a talk with my daughter and my grand kids again about this. I’m thinking the boy (now 18) should be tested for FH as well, even though his lipid panels have been very normal. Ha! The kids call me doctor memaw.

JFord
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JFord

“Compared with the reference group with LDL-C 190 mg/dL (4.9 mmol/L) and no mutation had a sixfold higher risk of CAD while those with both and LDL-C > 190 mg/dL and an FH mutation had a 22-wold increase risk of CAD.”

Do you happen to know if the “sixfold higher risk” and the “22-wold [sic] increase risk” is calculated using the relative risk ratio? I am guessing that it is and the absolute risk increase is significantly lower.

Axel F Sigurdsson
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Axel F Sigurdsson

Pretty good question.
However, as we are comparing two groups, the comparison is always going to be relative. We’re not talking about risk reduction, so relative vs. absolute risk reduction is not an issue here.
The calculation is pretty complex. Those with LDL-C 190, and 22.3 for the FH mutation positive with LDLC >190.

JFord
Guest
JFord

Thanks for the response. Indeed, if a hypothetical absolute 5 out of 100 CAD risk for the control group versus an absolute 30 out of 100 risk for the other group, that is patient and life significant. High relevance. But I sense the sixfold higher risk determined by these researchers is more a result of a statistical methodology that is not related to a true absolute risk measurement and comparison, nor necessarily relevant to patients in assessing their true risk. If a regression was involved, I doubt the sixfold increase would hold when looking at the actual absolute numbers. If… Read more »

Axel F Sigurdsson
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Axel F Sigurdsson

I agree with you JFord. In my opinion it’s too much statistical acrobatics. The result will often be a message that is hard to understand and that is not really useful for the practicing clinician or the patient.

Liz
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Liz

Hi Dr. Sigurdsson (and anyone else who cares to weigh in!), I am a fourth year American medical student trying to sort out my health issues before disappearing into the black hole of residency. I would love your feedback on my sort of odd lipid panel, if you could spare a moment! I am a healthy 28 year old woman. Normal BMI, baseline BP ~100/60, A1C 4.9%. Very active with crossfit and running. I’ve had high cholesterol for life (LDL > 160 since age 11 or so, now at age 28 > 180 – 200). This is consistent with just… Read more »

Axel F Sigurdsson
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Axel F Sigurdsson

Hi Liz I think the difference in LDCL-C here between Friedwald and the Iranian formula is a typical example of how LDL-C may be overestimated when TG’s are low. I would vote for the Iranian formula here. I think you’re spot on with the statin issue. I would not recommend statins here unless it’s proven by genetic analysis that you have FH. It is unlikely in my opinion, just as you said yourself, considering the absence of premature CAD in your family. And, as you’ve pointed out correctly, the high HDL-C and low TG’s is clearly a positive thing. So,… Read more »

Liz
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Liz

Hi Alex,

Thank you for providing a clear and quick answer! Really enjoying poring through your posts. Fingers crossed the FH panel is all negative.

Best,
Erin

Liz
Guest
Liz

And by Alex i mean Axel! 🙂

Axel F Sigurdsson
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Axel F Sigurdsson

It would really surprise me if it isn’t negative.
Best of luck Liz.

Erin Elbel
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Erin Elbel

So good news – all the FH testing (APOB, LDLR, LDLRAP1, PCSK9) was negative!

Lp(a) is elevated at 65, though. Do you have any thoughts on this? Considering starting niacin as it sounds like it lowers Lp(a) and has fewer side effects than statins as well as being a potent anti-inflammatory.

Liz
Guest
Liz

So good news – all the FH testing (APOB, LDLR, LDLRAP1, PCSK9) was negative!

Lp(a) is elevated at 65, though. Considering starting niacin as it sounds like it lowers Lp(a) and has fewer side effects than statins as well as being a potent anti-inflammatory. Are there any downsides to niacin if I can tolerate the flush?

Axel F Sigurdsson
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Axel F Sigurdsson
David Capparuccini
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David Capparuccini

Liz,

Where did you get your FH testing at? I want to get tested for it.

Also, I just posted my thoughts on Niacin. Not sure if Dr. Sigurdsson agrees or not.

I like the flush!

Cheers, David

Liz
Guest
Liz

Thanks, David and Dr. Sigurdsson!

David – Do you take it in the morning or night time? With food or without?

I got my testing from GeneDx – they were great to work with and really quick. They accept insurance and the co-pay is on a sliding scale, so most people are <$100 out of pocket. Has to be ordered by a doc still, though.

David Capparuccini
Guest
David Capparuccini

Thanks for the heads-up about GeneDX.

I ALWAYS take Niacin with food. It will flush the heck out of you without food. I usually take a baby aspirin beforehand, and it makes the flush not as bad.

All experts recommend starting with 100 mg, and then adding 100 mg more every day or so. Your body will build up to dosage. I did that and now I handle 2,000 mg a day easily. I take it in divided doses – 1,000 mg with breakfast and then 1,000 mg with lunch. So far, no blood sugar OR liver issues.

David Capparuccini
Guest
David Capparuccini

Dear Dr. Sigurdsson, I have been following your blog for a few months now and love it! Just want to encourage you to keep up the good work. I especially loved your post on the “Great Cholesterol Myth”. I am hoping that more people wake up to see what nonsense is being spewed out in that book. I even bought some of their supplements, but then finally realized it was a scam. OK, to the current post: I am a 36 year old male, and my Doctor (great primary care doctor) has been testing my lipids for years. My LDL-C… Read more »

David Capparuccini
Guest
David Capparuccini

Dear Dr. Sigurdsson, I have been following your blog for a few months now and love it! Just want to encourage you to keep up the good work. I especially loved your post on the “Great Cholesterol Myth”. I am hoping that more people wake up to see what nonsense is being spewed out in that book. I even bought some of their supplements, but then finally realized it was a scam. OK, to the current post: I am a 36 year old male, and my Doctor (great primary care doctor) has been testing my lipids for years. My LDL-C… Read more »

David Capparuccini
Guest
David Capparuccini

Dr. Sigurdsson, After re-reading your article I have another quick follow-up question/comment. If someone is identified as having high lp(a) and high ldl-c (and ldl-p) then should they always be treated with statins? From what I have gathered in speaking with various doctors the answer seems to be yes. However, is it worth is to check for FH gene? I asked my lipidologist and she said she used to test for FH gene, but the test is very expensive (over $ 1,000) and does not change how she would treat severe hypercholestermia. Also, for the past year I have been… Read more »

Axel F Sigurdsson
Guest
Axel F Sigurdsson

Thanks for the comment David. There are several important issues here. Obviously, I don’t have all the answers for you. I think FH is unlikely in your case because of the absence of premature coronary artery disease in your family. Another thing; a coronary calciums core of zero is associated with a very low risk. https://www.docsopinion.com/2016/10/17/targeting-statin-treatment-biolmage/ However, it has to be taken into consideration hat you are very young. We don’t know what your score will be 10 years from now. I agree that your Lp(a) is a concern. https://www.docsopinion.com/health-and-nutrition/lipids/lipoprotein-a/ Niacin and the new PCSK9 inhibitors are able to lower… Read more »

David Capparuccini
Guest
David Capparuccini

Dr. Sigurdsson,

Thank you very much for the wonderful and comprehensive reply! I very much appreciate it. I have decided for the sake of my children to take a genetic test to determine whether I have FH or not.

That said, what genetic tests do you recommend and where? I live in the United States.

Cheers! David

David Capparuccini
Guest
David Capparuccini

Dear Dr. Sigurdsson, I have been following your blog for a few months now and love it! Just want to encourage you to keep up the good work. I especially loved your post on the “Great Cholesterol Myth”. I am hoping that more people wake up to see what nonsense is being spewed out in that book. I even bought some of their supplements, but then finally realized it was a scam. OK, to the current post: I am a 36 year old male, and my Doctor (great primary care doctor) has been testing my lipids for years. My LDL-C… Read more »

David Capparuccini
Guest
David Capparuccini

Liz, I loved Dr. Sigurdsson’s article on Niacin! I have found that I can tolerate regular “flush” niacin really well. However, some people can’t. The only advise I have is IF you take Niacin make sure to check your liver enzymes and blood sugar as it can elevate both. I recommend “Cholesterol Control Without Diet!: The Niacin Solution” by Dr. William Parsons if you want to learn about Niacin, and how to use it. Dr. Parsons repeatedly emphasizes that Niacin at cholesterol-lowering doses requires medical supervision. https://www.amazon.com/Cholesterol-Control-Without-Diet-Solution/dp/0966256867/ref=sr_1_2?ie=UTF8&qid=1511826092&sr=8-2&keywords=The+Niacin+Solution I wish you success as I too have elevated Lp(a)! However, my lipidologist… Read more »

Liz
Guest
Liz

Thanks for this reply! I will give my PCP a heads up that I’m taking niacin… I think my cardiologist is not interested in seeing me any more given the negative FH testing and that I’m not interested in a statin right now (or in cutting out all dietary fat and cholesterol – he is pretty old school.) What monitoring does your lipidologist recommend?

I haven’t had the exact particle size of my lipids measured, but my low triglycerides (usually around 45-55) make me suspect the LDL would be on the bigger, fluffier side.

David Capparuccini
Guest
David Capparuccini

My lipidologist recommends that IF you have elevated lp(a) your ldl-particles should be less than 1,000. Ideally, between 700 to 1,000. OK, I forgot to write this yesterday, but you may want to consider fat reduction. Some people are hyper-responders to saturated fat and cholesterol. They more they eat the more they absorb. Some are not, but you might be. Total Cholesterol of 290 and LDL-C of 188 is no joke! There are numerous articles on the internet about this. If you want I can try go dig them up. Last, particle size is nonsense. It is ALL about particle… Read more »

Liz
Guest
Liz

Thanks for pointing me to the saturated fat/cholesterol hyper-responders situation. I definitely think that could be me. The good news is, I eat a lot of saturated fat now, so I can probably cut my intake quite a bit and see what difference that makes.

Re: measuring LDL-P.. interesting, I wonder why my cardiologist wasn’t on top of that with my lipid panel. Did you get it covered by insurance? Or did you get something like this out of pocket? https://www.walkinlab.com/nmrlipoprofilebloodtest.html

Ester
Guest
Ester

Hi Dr Sigurdsson, Very interesting blog indeed. I wonder if I have Familial Hypercholesterolemia (FH) and would love to hear your feedback. I am a 70 year old woman and have high cholesterol (total cholesterol >270) since the age of 40. I was put on a statin since age 45 and TC stayed in the range of 190 to 215. I stopped the statin 2 years ago. I did a blood test this month and the results are: Total Cholesterol 294 mg/dl LDL 205 mg/dl HDL 73 mg/dl Triglyceride 79 mg/dl Lp(a) 0.13 g/L Blood Pressure 110/70 HAB1C 5.4% hs-CRP… Read more »

Axel F Sigurdsson
Guest
Axel F Sigurdsson

Hi Ester

Thanks for the comment.
Only genetic testing can give you the answer.
However, the absence of premature coronary artery disease in your family would in my opinion suggest that you don’t have FH.

Ester
Guest
Ester

Thank you lots and lots for your feedback Dr Sigurdsson. I don’t have xanthelasma nor arcus cornealis. I have been taking statins for 15 years from age 53 to 68 and my LDL remained at 115 and HDL at 66 for these 15 years. Perhaps these 15 years have reduced my long term accumulative LDL burden. I stopped the statin 2 years ago. Now at age 70 with a Calcium Score = 141, LDL = 200, HDL = 73, Would it be necessary to take Statin again to lower risk? Is it true that Statin is not effective for old… Read more »

Ester
Guest
Ester

Thank you lots and lots for your feedback Dr Sigurdsson. I don’t have xanthelasma nor arcus cornealis. I have been taking statins for 15 years from age 53 to 68 and my LDL remained at 115 and HDL at 66 for these 15 years. Perhaps these 15 years have reduced my long term accumulative LDL burden. I stopped the statin 2 years ago. Now at age 70 with a Calcium Score = 141, LDL = 200, HDL = 73, Would it be necessary to take Statin again to lower risk? Is it true that Statin is not effective for old… Read more »

Ester
Guest
Ester

Dear Dr Sigurdsson, Can you feedback please? I have substantially reduced the number of questions. I don’t have xanthelasma nor arcus cornealis. I have been taking statins for 15 years from age 53 to 68 and my LDL remained at 115 and HDL at 66 for these 15 years. Perhaps these 15 years have reduced my long term accumulative LDL burden. I stopped the statin 2 years ago. Now at age 70 with a Calcium Score = 141, LDL = 200, HDL = 73, Would it be necessary to take Statin again to lower risk? Is it true that Statin… Read more »

Ester
Guest
Ester

Dear Dr Sigurdsson, I would like to ask you just one question please. You are a smart doctor and probably the only one who is conservative on statins. I really would love to hear your feedback which would give me peace of mind. Would you kindly feedback please? I don’t have xanthelasma nor arcus cornealis. I have been taking statins for 15 years from age 53 to 68 and my LDL remained at 115 and HDL at 66 for these 15 years. Perhaps these 15 years have reduced my long term accumulative LDL burden. I stopped the statin 2 years… Read more »

Axel F Sigurdsson
Guest
Axel F Sigurdsson

Dear Ester. I have to remind you that my blog is for general informational purposes only and does not constitute the practice of medicine, including the giving of medical advice, and no doctor/patient relationship is formed. The content of this blog is not intended to be a substitute for professional medical advice, diagnosis, or treatment. That said, I can tell you that I agree with you that 15 years of statin treatment has surely reduced your accumulative LDL-C burden. In your case, taking a statin drug is not a necessity but rather a choice. The absence of cardiovascular disease among… Read more »

Ester
Guest
Ester

Dear Dr. Sigurdsson, Thank you lots and lots for your feedback. I understand that no doctor/patient relationship is formed here and everything you said. From reading your blog, you have a great heart to help people. That’s why I really look up to you and wish for your opinion. I have been eating healthy and exercising all the time. The issue regarding whether or not to take statins is always on my mind. Can you give me your opinion please whether or not it is a good choice to take statin to lower risk? I am not sure if the… Read more »

Ester
Guest
Ester

Dear Dr. Sigurdsson, I’d like to ask you a scientific question , would you be able to feedback please? For a 70 year old woman with high cholesterol (LDL = 200, HDL = 73) as the only risk, If her Calcium Score (CAC) = 0 , then I think the risks of taking a statin outweights the benefits so it is better not to take the statin. However if her CAC > 400, then I think the benefit of taking a statin outweights the risks so it is better to take the statin. The difficult question is what if the… Read more »

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