Rare Disease Report

NLA Scientific Session Day 1 - HoFH Explained

MAY 02, 2014
James Radke

On the first day of the 2014 National Lipid Association (NLA) Scientific Sessions, Raul D. Santos, MD, MSc, PhD, provided a comprehensive overview explaining familial hypercholesterolemia (FH), including a detailed explanation on how best to detect, diagnose, and manage homozygous FH (HoFH).
Dr. Santos is director of the Lipid Clinic of the Heart Institute (InCor), University of São Paulo, Brazil, associate professor of the Discipline of Cardiology, University of São Paulo Medical School, and scientific advisor in Preventive Cardiology, Hospital Israelita Albert Einstein, São Paulo.

Familial Hypercholesterolemia

 FH is a genetic condition that can be either heterozygous (HeFH), which is very common, or HoFH, which is very rare. Many guidelines are available for FH, including NLA’s guidelines.

Common to both HoFH and HeFH are severe dyslipidemia (eg, low-density lipoprotein cholesterol [LDL-C] >190 mg/dL), early cardiovascular disease, cutaneous stigmata, and a family history. Where HoFH and HeFH differ is in the genetics (HoFH has two mutations of the LDL-R gene, HeFH has one); the prevalence (HoFH, 1 in 1 million; HeFH, 1 in 600); and the severity (HoFH is a more serious condition, with death often occurring by age 20, if left untreated).

Case Study

Of concern to Dr. Santos is that many patients with HoFH may not be diagnosed young enough to get properly treated. To illustrate how easy it is to miss a diagnosis of HoFH, Dr. Santos talked about a patient who was referred to his clinic. He was a young adult male, asymptomatic with extensive xanthomata. He presented to the lipid clinic at the age of 20 years. What was surprising about this young man was that he had had the signs of HoFH as early as 3 years of age, but he was never diagnosed or tested for this rare disease. At the age of 3 years, his parents stated that he had nodules in the tendons of his hands, and over time similar lesions were observed on the tendons of his elbows, knees, and feet. However, for the most part, he was asymptomatic and enjoyed playing soccer. Further, since the age of 10 years, he had had a history of high cholesterol. A family history revealed that his mother also has a history of hypercholesterolemia, and that he had an uncle and a cousin who had died suddenly in their 20s and 30s.

Laboratory results from the 20-year-old patient revealed the following:
  • LDL-C 710 mg/dL
  • TGs 221 mg/dL
  • HDL-C 33 mg/dL
  • ECG and x-ray normal
After reviewing the lab results, the patient was prescribed 20 mg atoravastatin and 10 mg ezetimibe and after 4 months, his lab results showed his lipids were still high but they had been reduced by approximately 50% (typical for HoFH).
  • LDL-C 352 mg/dL
  • HDL-C 25 mg/dL
In addition, a genetic test showed the patient was homozygous for the LDL-R mutation A54OT in exon 11.

Diagnosing HoFH

Using the patient as an example, Dr Stantos described the clinical criteria to diagnose HoFH:
  1. Genetic confirmation of 2 mutant alleles at the LDL receptor, ApoB, PCSK9, or ARh adaptor protein gene locus.
  1. an untreated LDL-C >500 mg/dL or treated LDL-C >300 mg/dL plus
  • cutaneuous or tendonous xanthomas before age 10 years
  • elevated LDL-C levels in both parents consistent with HeFH

Natural History

Currently, the natural history of HoFH is not completely known. However Dr Santos did note some traits common to many patients with HoFH:
  1. Early xanthomata
  2. Aggressive and early-onset coronary heart disease
  3. Widespread atherosclerosis
  4. Aortic valve and supra-aortic disease
  5. Lots of suffering
  6. Early death (eg, age 20 years if not treated)


Statins can lowers LDL-C levels by 50%, and Dr. Santos said that they can extend life by 10 to15 years. Recently approved orphan drugs (Kynamro, Juxtapid) lower LDL-C levels much further, but survival data for these two drugs have not been generated yet.

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