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Familial hypercholesterolemia guideline urges early diagnosis, treatment by specialists
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A new guideline from the European Atherosclerosis Society recommends quick diagnosis and referral to specialist centers for patients with homozygous familial hypercholesterolemia.
Patients diagnosed with homozygous familial hypercholesterolemia (HoFH) should begin lifestyle interventions and maximal statin therapy upon diagnosis, according to the guideline written by Marina Cuchel, MD, PhD, and colleagues from the European Atherosclerosis Society’s consensus panel on familial hypercholesterolemia.
Ezetimibe (Zetia, Merck) and other lipid-modifying therapies may also be appropriate in this population, as might be adjunctive lipoprotein apheresis, according to the panel.
People with HoFH have mutations in both alleles of the LDLR gene that encodes the LDL receptor, which makes it difficult for them to bind and internalize LDL particles, and other mutations may be present in some patients. If untreated, those with HoFH may achieve LDL levels >500 mg/dL, may develop atherosclerotic CVD by age 20 years and may not survive past age 30 years, according to the authors.
“Unfortunately, HoFH is typically diagnosed when considerable coronary atherosclerosis has already been developed, emphasizing the need for optimization of treatment in childhood,” Cuchel, from University of Pennsylvania’s Institute for Translational Medicine and Therapeutics, and colleagues wrote.
Diagnosis of HoFH
The guideline states that the best way to diagnose HoFH is through genetic confirmation of two mutant alleles at the LDLR, APOB, PCSK9 or LDLRAP1 gene locus.
However, the authors wrote, genetic diagnosis may not be possible for all patients, in which case clinical criteria must be applied. These include untreated LDL >500 mg/dL, treated LDL ≥300 mg/dL together with cutaneous or tendon xanthoma before age 10 years or untreated elevated LDL levels consistent with heterozygous familial hypercholesterolemia (HeFH) in both parents. Lower levels of LDL may not necessarily preclude a diagnosis of HoFH, they wrote, adding that patients with a suspected diagnosis should be referred to a specialized center for proper comprehensive management.
The panel recommended that once a diagnosis of HoFH has been made, reverse cascade screening should be conducted in parents and relatives to identify others with HoFH or HeFH.
Those diagnosed with HoFH should be screened regularly for subclinical aortic disease and CHD, according to the guideline. Patients should receive a comprehensive CV evaluation at diagnosis and an annual Doppler echocardiographic evaluation of the heart and aorta, and if available, they should receive coronary CTA every 5 years (or more frequently if clinically indicated), Cuchel and colleagues wrote.
Treatment of HoFH
Patients with HoFH should be encouraged to eat a heart-healthy diet low in cholesterol and saturated fats, but even with strict adherence, diet can have little effect on the severity of hypercholesterolemia. Physical activity is encouraged, and the primary aim of therapy should be to reduce LDL.
Lipid-lowering therapy should be initiated as soon as possible, with LDL targets of <100 mg/dL in children and <70 mg/dL in adults with clinical atherosclerotic CVD, although clinicians should take into account the risks and benefits of such aggressive targets, according to the panel.
Statins have been shown to reduce CV mortality and all-cause mortality in patients with HoFH and should be the first line of medical therapy; however, they tend to reduce LDL by 10% to 25% in most patients with HoFH, and therefore addition of ezetimibe therapy, which can reduce LDL by another 10% to 15%, may be necessary, Cuchel and colleagues wrote.
Other medications, including bile acid sequestrants, niacin, fibrates and probucol, have been successfully used in combination with statins in this patient population, according to the panel. Novel medical therapies such as lomitapide (Juxtapid or Lojuxta, Aegerion Pharmaceuticals) and mipomersen (Kynamro, Isis Pharmaceuticals) may be promising treatments for patients with HoFH, as might PCSK9 inhibitors, which are still in clinical studies.
Extracorporeal removal of LDL, through processes such as lipoprotein apheresis, is an important adjunctive treatment in this population, Cuchel and colleagues wrote, noting that a single treatment can decrease LDL levels by 55% to 70%, and subsequent weekly treatments can push LDL levels down to close to normal.
Liver transplantation, either alone or in combination with heart transplantation, is another treatment option, but comes with obvious drawbacks such as high risk for post-surgical complications and mortality, the panel wrote.
Psychological support should be integrated into routine care, surgery may be considered to remove large xanthomas, and contraception and pregnancy should be discussed with female patients with HoFH, the panel wrote, noting that hormonal contraception is generally contraindicated in this population.
Disclosure: The panel is supported by unrestricted educational grants from Aegerion Pharmaceuticals, Amgen, AstraZeneca, Genzyme, Hoffmann-La Roche, Kowa Europe, Novartis and Sanofi-Aventis/Regeneron. See the full guideline for a list of the panel members’ relevant financial disclosures.
Perspective
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Joshua W. Knowles, MD, PhD, FAHA, FACC
The guideline is very timely. One important point is that modern genetic studies have shown that HeFH and, therefore, HoFH are more frequent than was originally thought. In the paper, the lower bound of the estimate for prevalence HoFH is 1 in 1 million and the upper bound is 1 in 160,000. The actual truth is still a bit of a mystery, and most of the data that have emerged are for white/European populations. Studies in other populations certainly need to be done. The upper limit of normal of 1 in 160,000 is still to be confirmed in multiple populations. The largest study was in the Dutch population, where there was an estimated frequency of 1 in 300,000. We don’t know the right answer, but it certainly is not as infrequent as we used to think.
For these severely affected patients, the emergence of new therapies is very important. Two are on the market and more are coming soon.
The guideline is largely transferable to the United States. I don’t think there is a lot of difference from Europe, other than that genetic testing for FH is much more frequent in some European countries than it is in the United States. However, I think it is inevitable that genetic testing for FH will become more frequent in the United States. The cost of genetic testing is coming down sufficiently, and evidence is emerging that it can be useful not only for HoFH but also for HeFH. There are still some issues about cost and availability and applicability, but I think it will become more frequent, if perhaps not universal.
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