Familial Hypercholesterolemia (Part 1): Diagnosis and Screening Challenges

Eric Bruckert, MD, PhD; Boris Hansel, MD


June 03, 2015

Editor's Note:
The following is an edited, translated transcript of a conversation taped in May 2015 between Boris Hansel, MD, endocrinologist-nutritionist, and Eric Bruckert, MD, PhD, a lipid management specialist, in France.

Dr Hansel: Today we're going to talk about familial hypercholesterolemia with Prof Eric Bruckert, director of the Endocrinology Department at La Pitié-Salpêtrière Hospital in Paris, who sees patients with severe dyslipidemias on a daily basis, including familial hypercholesterolemias.

This conversation is in two parts. In the first part, we will define familial hypercholesterolemia and discuss its diagnosis and screening. In the second one, we will talk about treatment, specifically dietary measures and pharmacologic treatments.

Defining Familial Hypercholesterolemia

Dr Hansel: Hypercholesterolemia can be defined as a low-density lipoprotein (LDL) cholesterol level greater than 160 mg/dL. In terms of its prevalence in France, approximately 25% of the adult population meets this definition [as does 32% of the population in the Unites States[1]]. It is therefore fairly common, and most of these individuals have a mild form.

However, there are also more severe forms, such as familial hypercholesterolemia. It's rare but not at all exceptional, given that it affects about 1 person in 500. It could be a bit more common; some figures are as high as 1 in 250. [Editor's note: In the United States, a recent study showed that the overall US prevalence of familial hypercholesterolemia is 1 in 299.[2]]

How does one concretely, clinically, and on the basis of laboratory tests distinguish familial hypercholesterolemia from "ordinary" or mild hypercholesterolemia?

Dr Bruckert: It is, in fact, important to distinguish between these two forms of hypercholesterolemia, whose clinical presentations are very different. Familial hypercholesterolemia, whose prevalence is traditionally 1 in 500, is a form with a very somber cardiovascular (CV) prognosis because, on average, the CV risk is 13-fold higher. This risk is, for example, much higher than that posed by diabetes. It's an autosomal dominant form—which is what defines it—characterized by a cholesterol level that is, on average, twice the normal value from birth. In young people (at age 20 years), the median LDL cholesterol level is 110 mg/dL. After that, as people age, it increases. Basically, it can be said that the average LDL cholesterol level in this form is close to 200 mg/dL.

Dr Hansel: Is the LDL cholesterol level alone sufficient to speak of familial hypercholesterolemia, or are there other diagnostic criteria?

Dr Bruckert: Actually, there are other criteria, which may include:

  • Family history: It's a form characterized by autosomal dominant transmission. Therefore, in all cases, one of the two parents has severe hypercholesterolemia. Often, in these families, there is also a CV history. Therefore, family history is key.

  • The clinical examination: These patients have tendon xanthomas, which increase in size with age. Most often, young patients don't have any, while close to one half of those aged 30-40 years do.

Dr Hansel: These xanthomas, these swellings, which can be easily palpated on the Achilles tendons and possibly on tendons in the upper limbs, are caused by the accumulation of cholesterol over time.

Dr Bruckert: Exactly.

Figure. Tendon xanthomas

The next to look at is:

  • The laboratory criterion: an elevated LDL cholesterol level. What's not adequately explained is that this elevation exists from birth. Let's take the case of a patient who had a normal cholesterol level at the age of 20 years and an elevated cholesterol level at the age of 30 years. It's practically never a familial form. Rather, it's a polygenic form. On the other hand, in the case of a significantly elevated cholesterol level from birth, there's a very strong probability that the patient has a familial form.

Dr Hansel: When we talk here about familial forms, we mean genetic, and you spoke about an autosomal dominant form. Patients with one mutated allele will present with an elevated cholesterol level, while those with both alleles mutated will have very severe forms, although, of course, they are much rarer. Are the genetic mechanisms known? What genes are involved in these familial forms?

Dr Bruckert: We know which gene is involved in about 90% of the familial hypercholesterolemias characterized by autosomal dominant transmission in France. In the vast majority of cases, it's the gene that codes for the LDL receptor. Practically 90% of the forms identified involve a mutation of the LDL receptor.

There are two other causes: a mutation in apolipoprotein B, which is the ligand for the LDL receptor, and a mutation of a protein called PCSK9.

Dr Hansel: This discovery [the mutation of the gene that codes for the PCSK9 protein] was actually made in France by our colleague, Prof Catherine Boileau (Hôpital Bichat, Paris). We'll talk about this mutation again in the second part of this conversation because there are treatments that target this pathway.

When Should a Genetic Test Be Ordered?

Dr Hansel: Presently, is ordering a diagnostic genetic test warranted as soon as one suspects a familial form?

Dr Bruckert: Yes. A diagnostic genetic test is essential in the vast majority of cases. Why? Because it's the only way to confirm the diagnosis. Furthermore, giving the patient a genetic diagnosis significantly improves management, family screening, and therapeutic compliance.

Dr Hansel: It's therefore a method of treatment education. Is that right?

Dr Bruckert: Yes. And this has a real impact. My explanation is that when hypercholesterolemia is identified as being of genetic origin, this probably removes a burden of guilt. It's known that there is a heavy burden of guilt in diabetes and in most hypercholesterolemias. A genetic diagnosis facilitates management a great deal.

Dr Hansel: Presently, can this diagnostic test be performed on a routine basis?

Dr Bruckert: In France, the test is fully covered by the Rare Diseases plan. However, one has to contact an accredited laboratory (there are five of them in France). The diagnosis can be made fairly easily because most laboratories will agree to send a tube for having this genetic test performed at an accredited laboratory. Therefore, once the consent form is signed (for, in practice, the physician or biologist has to obtain consent), it's relatively easy.

Dr Hansel: Should we propose a genetic test as soon as a patient's LDL cholesterol level exceeds 220 mg/dL, which is twice the normal value, particularly in children?

Dr Bruckert: The genetic test can be considered extremely useful when the LDL cholesterol is greater than 190 mg/dL and the patient has a family history suggestive of an autosomal dominant form. When these two criteria (family history and LDL >190 mg/dL) are used, a mutation is found in 50% of cases. It's therefore quite cost-effective.

[Editor's note: In US guidelines, cascade screening does not necessarily incorporate genetic testing, although DNA analysis is considered in some cases as useful or is recommended when resources are available.[3]]


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