Familial Hypercholesterolemia — Managing a Potentially Devastating Disorder

Baum, Seth J., MD, FACC
Preventive and Integrative Cardiology
Medical Director, Women’s Preventive Cardiology
Christine E. Lynn Women’s Health & Wellness Institute
Boca Raton Regional Hospital Also by this Author 

Familial Hypercholesterolemia (FH) is a genetic disorder, which causes premature atherosclerotic cardiovascular disease, and can lead to serious cardiac events in young patients, even those under 10 years of age.

Dr. Seth Baum, Medical Director, Women’s Preventive Cardiology, Boca Raton Regional Hospital, and Chief Medical Officer, MB Clinical Research, discusses the importance of recognizing FH early in life, to enable timely intervention and reduce the risks associated with a potentially life-threatening condition, which affects up to 1 in 200 people and is diagnosed in less than 1% of patients in most countries.1-2

Defining FH

“FH is a genetic cause of high cholesterol,” says Dr. Baum.  “In the early seventies Brown and Goldstein described FH as a genetic disorder of high cholesterol that's autosomal dominant and caused by LDL receptor mutations.3-4 In the heterozygous form of FH, an individual has one mutation - one LDL receptor mutation, one abnormal allele.  In the homozygous form, both alleles have mutations. The homozygous form is typically more severe than the heterozygous form.”         

The challenge with describing FH, cautions Dr. Baum, is that its definition is constantly evolving. “It’s now been found that in addition to an LDL receptor mutation, people can have mutations in multiple other genes that can cause FH, such as in PCSK9 or in apolipoprotein B-100 (apoB-100), so it's growing in complexity.”

“It’s important to define FH and separate it from non-genetic causes of high cholesterol, as it is autosomal dominant and so can be passed on to one's children very readily,” continues Dr. Baum. “We need to identify these people early on so that we can then manage and treat as soon as possible, because the earlier you treat them, the better their outcomes.”

Based on its original description the condition seemed very rare - 1 in 500 were heterozygous and 1 in a million were homozygous.  But in recent years, data have emerged showing that the prevalence is much closer to 1 in 200 for heterozygous and about 1 in 160,000 for the homozygous form.1-2

Clinical Significance

The main concern for someone with FH is the potential for vascular disease, typically heart attack or angina. There is a risk of stroke and those with homozygous FH can sometimes develop valvular heart disease, like aortic stenosis or supravalvular aortic stenosis. Those with a very serious condition could develop disease well before the age of 10 and can suffer a cardiac event at a very young age. More commonly, a cardiac event, such as premature heart attack or premature angina, occurs later in life. “I have a number of patients who either had events or required a procedure, such as stent placement or a bypass, in their late teens, twenties or thirties,” notes Dr. Baum.        

Identifying the FH Patient – Diagnostic Challenges

“To diagnose the disorder, it’s very important to understand the patient’s history and the context of their condition,” says Dr. Baum. “For instance, if you're looking at an eight year-old child with an LDL of 160, and that child has a family member with FH, then that child most likely has FH. The standard image of the FH patient was traditionally somebody with large cutaneous xanthomas on their elbows or on their extensor tendons, their Achilles tendons, or with a corneal arcus, a greyish ring around the outer aspect of the cornea. But the reality is that there's a tremendous disparity of presentations - some people have none of these signs, while others can have several - and it becomes very difficult to diagnose simply on that basis. We’ve come to understand that the phenotypic expression of the disease, in other words how high the LDL is, or whether the person has vascular disease at a young age, or has xanthomas, is variable.  You can have some people with very high LDL's who don't have these issues or some who have pathogenic mutations, whose LDL's are not as high as you would expect. There's a lot more complexity than was originally recognized.”

A number of systems are available to assist in making a diagnosis of FH. “Most of us use the Dutch Lipid Clinic Network criteria,” says Dr. Baum, “ which is based on a number of different metrics entered into an equation to determine whether a patient has possible, probable, or definite FH.  There are also the Simon Broome Register criteria, and the MedPed program, which is not widely used. Most physicians will make the diagnosis on clinical grounds, making an assessment utilizing a range of criteria. Is the LDL very high for a given age and sex of your patient? Does that patient have premature vascular disease? Do the parents have either premature vascular disease or very high cholesterol?  You would obviously also take into account any signs found on a physical exam such as xanthomas. You can also look at the response to therapies, as people with FH will very often have a blunted response to standard lipid lowering therapy.  So, if you prescribe a statin anticipating a 50% reduction or greater in LDL cholesterol and you achieve a 10 or 20% reduction, you should consider a diagnosis of FH.  So, it’s a matter of pulling together all this information and making a diagnosis.”

Laboratory Testing

The value of genetic testing for low density lipoprotein receptor (LDLR) and APOB gene defects, and more recently for PCSK9 gene mutations, in assessing FH and performing cascade screening has now been recognized.5-7 Dr. Baum also believes it is important to test for Lp(a). “I personally test Lp(a) in every patient,” says Dr. Baum. “About 20% of people have a high Lp(a) level, which causes problems on two levels.  One is that it's atherogenic, so it causes plaque, and the other is it's thrombotic, so it causes clotting. Not only is Lp(a) elevation more common in FH patients than in the general population, but these patients can be very sick with much more aggressive vascular disease. So, it's very important to check Lp(a) in all FH patients, though I would recommend checking Lp(a) in every patient. In my practice there are a good number of patients with normal cholesterol and an elevated Lp(a) who have premature and aggressive vascular disease.

Treating FH

“The treatment for FH patients starts the same way as treatment for anybody with high cholesterol. This consists of lifestyle changes – diet and exercise to achieve optimal weight - and standard lipid therapy, initially with statins,” notes Dr. Baum. “There may be a need for add-on therapy with ezetimibe or a bile acid sequestrant, such as Welchol, or both, and sometimes niacin may be added to the regimen. We then monitor the patient’s LDL level. If it has not declined sufficiently, and the patient has FH, the next therapy would be lipoprotein apheresis, which is available in about 60 centers in the country. It’s unfortunate that access to this therapy is limited as it lowers the LDL about 70% after each treatment. It does rebound back to just under the initial LDL, so it has to be performed repeatedly – usually every other week, and once a week with very sick patients - but it is a very good therapy and there are data demonstrating that it reduces events.” 

For homozygous FH patients, there are two drugs that have been approved.  One is lomitapide, or Juxtapid®, an oral medication that is a microsomal triglyceride transfer protein (MTP) inhibitor. The second one is mipomersen, also called Kynamro®, which is an antisense oligonucleotide against the messenger RNA for apoB-100, but it is not approved for patients undergoing lipoprotein apheresis therapy. Both lomitapide and mipomeresen require the prescriber to have Risk Evaluation Mitigation Strategy (REMS) certification before use.

“Before determining therapy, the clinician has to try to differentiate the homozygous from the heterozygous FH patient, which can be extraordinarily challenging, due to associated complexities and ambiguities,” says Dr. Baum.  “In fact, we recently discussed the doctor's dilemma in making that diagnosis in an editorial in the Journal of Clinical Lipidology.”8    

FH Foundation – Identifying FH Patients Through Registry and Screening

The FH Foundation is an organization focused on increasing the rate of FH diagnosis and encouraging proactive treatment of the disease. It operates the only active national familial hypercholesterolemia registry, the Cascade FH Registry, and has launched an initiative called Find FH, which uses big data and machine-learning algorithms to identifythose people who likely have FH. “Starting in the fall of 2015, we're going to start an active cascade screening program,” says Dr. Baum, who is a board member of the foundation.  “With this program, we will identify the index case, the first case, and then we look for the first degree relatives, the second degree relatives, and third degree relatives to identify as many people as possible. In the Netherlands, where this was achieved very effectively, eight additional people with FH were identified for every initial case. For our cascade program we have on our team somebody who actually ran the Netherlands Cascade FH program.

The FH Foundation has been successful in having an ICD10 code be considered for both the heterozygous and homozygous forms of FH. It is also a resource for patients to find doctors who are experienced in managing patients with FH.

The Need for Greater Awareness

Dr. Baum concludes by highlighting the need for greater awareness of FH. “I would say that the biggest problem is the lack of education or understanding among healthcare practitioners and patients alike as to the prevalence of FH,” he says. “Since physicians thought it was such a rare condition, they felt it was highly unlikely they would ever see an FH patient in their practice. But with a prevalence of 1 in 200, there is a significant number of FH patients in everybody's practice. Due to the lack of awareness a very high proportion of FH patients remain undiagnosed. In fact, a recent European paper suggested that fewer than 1% of FH patients have been diagnosed in most countries.”1-2




  1. Nordestgaard BG, Chapman MJ, Humphries SE et al.European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-3490. doi:10.1093/eurheartj/eht273
  2. Cuchel M, Bruckert E , Ginsberg HN Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart. Published online 16 August 2013. http://eurheartj.oxfordjournals.org/content/34/45/3478  Accessed February 26 2015
  3. Brown MS, Goldstein JL. Familial Hypercholesterolemia: Identification of a Defect in the Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity Associated with Overproduction of Cholesterol. Proc Natl Acad Sci U S A. 1973 Oct; 70(10): 2804–2808.
  4. Brown MS, Goldstein JL. Familial Hypercholesterolemia: Defective Binding of Lipoproteins to Cultured Fibroblasts Associated with Impaired Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity. Proc Natl Acad Sci U S A. 1974 Mar; 71(3): 788–792.
  5. Scriver CR, Beaudet AL, Sly WS et al.Familial hypercholesterolemia.In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease.8th ed. New York: McGraw-Hill Information Services Company; 2001. p. 2863-2913.
  6. Izar MC, Valéria A Machado VA, and Francisco A Fonseca FA Genetic screening for homozygous and heterozygous familial hypercholesterolemia. Appl Clin Genet. 2010:3 147–157.
  7. van Aalst-Cohen ES, Jansen ACM, Tanck MWTet al. Diagnosing familial hypercholesterolaemia: the relevance of genetic testing Eur Heart DOI: 2240-2246 First published online: 6 July 2006. http://eurheartj.oxfordjournals.org/content/27/18/2240 Accessed February 26 2015
  8. Baum SJ, Sijbrands EJG, Mata P, Watts GF. The doctor's dilemma: Challenges in the diagnosis and care of homozygous familial hypercholesterolemia. Journal of Clinical Lipidology. Published Online: September 18, 2014. http://www.lipidjournal.com/article/S1933-2874(14)00329-8/abstract  Accessed February 26 2015


Juxtapid is a trademark of Aegerion Pharmaceuticals, Inc

Kynamro is a trademark of Genzyme Corporation