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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