August/September 2020 Issue
Familial Hypercholesterolemia
By Densie Webb, PhD, RD
Today’s Dietitian
Vol. 22, No. 7, P. 50
Here’s an update on diagnosis, treatment, and nutrition interventions.
Keeping cholesterol blood levels within a healthy range is an important measure for reducing the risk of CVD. While there are several lipids, including triglycerides and HDLs, that determine risk, an elevated LDL cholesterol level is highly correlated with CVD risk. The lower the LDL number, the better; less than 100 mg/dL is considered optimal for most people. An LDL level of 160 to 189 mg/dL is considered high risk.1 Dietary changes, weight loss, and regular physical activity often can lower levels, but if these efforts don’t do enough, medications, such as statins, can be prescribed.
However, for about 1 out of every 200 to 250 adults who are affected by a genetic condition known as familial hypercholesterolemia (FH), LDL levels can soar to 500 mg/dL or higher, all but guaranteeing CVD and, if left untreated, a significantly shortened life expectancy.2,3
What Is FH?
FH is an inherited genetic defect that affects how the body recycles LDL cholesterol, causing levels of LDL in the blood to build up and remain elevated. “It is characterized by inflammation, oxidative stress, and an immune response overlayed by a genetic predisposition and modified by epigenetics,” says Sonya Angelone, MS, RDN, owner of Angelone and Associates, a nutrition consulting company based in San Francisco, and a spokesperson for the Academy of Nutrition and Dietetics.
Angelone explains that oxidized LDL cholesterol gets into the endothelial layer of arteries, where it’s acted upon by macrophages and monocytes, leading to endothelial constriction, hypertension, and atherosclerotic lesions.
While most everyone’s LDL levels increase with age, people with FH have high LDL levels their entire lives, which, if not treated, will increase even more over time. FH can be inherited from one parent (heterozygous FH) or, in rare instances (about 1 in 160,000 to 1 in 1,000,000), from both parents (homozygous FH).4
If both parents carry the FH gene, their children will have FH. People with homozygous FH can have extraordinarily high LDL levels and are at even greater risk of coronary heart disease (CHD) and death than those with heterozygous FH. Homozygous FH is much more difficult to treat adequately, and people with homozygous FH can suffer from cardiac events even before the teen years.5
FH, which affects men and women equally, impacts children and adults.6 If left untreated, FH can lead to aggressive and early heart disease, heart attacks, and strokes. According to the Familial Hypercholesterolemia Foundation, individuals with FH have a 20 times higher risk of heart disease than the general population. Certain populations, including French Canadians, Ashkenazi Jews, Lebanese, and South African Afrikaners, have a higher prevalence of FH. In these populations, 1 in every 67 people has FH.7
FH Misconceptions
Two of the most common misconceptions about FH is that it’s uncommon and not risky, says Joshua W. Knowles, MD, an assistant professor of medicine at the Stanford University Medical Center. The reality, he says, is that FH is common and poses an unusually high risk of CVD. In fact, the Centers for Disease Control and Prevention now considers FH a major public health concern.8 One out of every 200 to 250 adults is affected worldwide, and the FH Foundation estimates that between 600,000 and 2 million Americans are affected.
Amy Reisenberg, MS, RDN, CDE, a clinical dietitian in cardiology at Stanford Health who works with Knowles, says patients with FH often think lifestyle modifications, including dietary changes, aren’t necessary, because they’re genetically fated to have high cholesterol.
Diagnosis
Screening for FH involves assessment of cholesterol concentrations in the blood, accompanied by an inspection for physical signs of FH, such as xanthomas, and evaluation of family history. Xanthomas are fatty deposits that are particularly noticeable around tendons in the hands, knees, Achilles tendons, and elbows, and under the skin around the eyes.9
Knowles, who volunteers for the FH Foundation, says it’s a problem that more than 90% of people with FH haven’t been diagnosed. “Untreated men have a 50% risk of myocardial infarction by age 50, untreated women a 30% chance by age 60,” he says. Of those who are diagnosed, Knowles says the diagnosis on average occurs in middle age (after age 45), and 20% to 30% aren’t diagnosed until after a cardiac event.
The American Academy of Pediatrics recommends that if a family has a pattern of heart attacks or heart disease in men before age 55 or in women before age 65, children in that family should undergo cholesterol testing as early as age 2, and before age 10.5 The FH Foundation says that holds true for anyone who has a family member with FH.
For many people, the first sign of FH is a heart attack or a stroke. Knowles says, “With proper early diagnosis and treatment, life expectancy is essentially normalized.” While it’s recommended that first-degree relatives of FH patients get tested, he says that seldom happens.
Even more rare is children being diagnosed after having their lipids tested. That’s because less than 5% of kids get lipid screening, according to Knowles.
If anyone in a patient’s family has had a heart attack, needed a stent, or had bypass surgery before the age of 55 for men or before the age of 65 in women, the FH Foundation says they should have a lipid profile performed.
Treatment
The goal of treatment is to target inflammation, oxidative stress, and the immune response. “The first line of treatment is always statins (eg, Lipitor, Crestor, Zocor, Mevacor), which are sufficient in 50% to 60% of patients,” Knowles says.
Statins can lower LDL cholesterol by 50% or more,8 but, in Knowles’ experience, “20% to 30% of FH patients require a secondline agent, such as Zetia, which works by reducing the amount of cholesterol absorbed by the body. About 20% require a third-line agent, which is usually a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.” PCSK9 inhibitors (Praluent and Repatha) are injectable drugs that target a protein that interferes with the clearance of cholesterol in the blood. Side effects and cost are the two biggest obstacles in taking these drugs; side effects vary greatly among individuals and cost differs among health insurance policies. Statins are available in generic form and are the least expensive medication. Zetia is available as a generic, although it isn’t always covered or may require a high copay. There are no generic PCSK9 inhibitors, so they’re typically expensive.
According to the American Heart Association, slightly less than 10% of FH patients resist treatment recommendations. An estimated additional 10% are intermittently compliant.3 That means approximately 1 out of every 5 FH patients doesn’t fully follow medical and dietary guidance to reduce CHD risk.
Most FH patients respond to cholesterol-lowering medications, but there are times when even those medications are ineffective. In those cases, doctors can perform a procedure called lipoprotein apheresis in patients as young as age 3. Lipoprotein apheresis is a 1 1/2- to three-hour procedure that removes LDLs from the blood.8
Since the cholesterol will build up again over time, the procedure may be required every week to every other week. While the procedure is safe and most patients tolerate it, it can be disruptive, causing patients to miss school or work and requiring them to drive long distances—there are only 60 lipoprotein apheresis centers in the United States.8
Studies have found significant reductions in mortality from CHD in patients who take statins, but many aren’t being treated adequately.10 Because of their existing high risk of CHD, patients with FH can’t be recruited to participate in randomized controlled trials involving placebo vs lipid-lowering therapies. However, FH registries that track patients over the long term have provided evidence regarding the efficacy of statin treatment.
There are several supplements being promoted as treatments for high cholesterol, but, Angelone says, “supplements are rarely recommended by physicians.” Reisenberg says she gets asked about phytosterols but doesn’t recommend using any of the vegetable oil spreads as a vehicle for getting phytosterols because often they contain palm oil or palm kernel oil. She does, however, sometimes recommend psyllium husk powder as a source of soluble fiber to lower cholesterol. Since psyllium husk powder can interfere with medication absorption, she recommends taking it either two hours before or after medications.
Dietary Management
While it’s true that people with FH produce more LDL cholesterol than normal, there are lifestyle modifications, including dietary changes, that can make a difference. “Dietary interventions are key and work hand in hand with medical management of FH,” Reisenberg says. “Typically, with a good diet and exercise we can help patients avoid having to take second- or third-line medications.”
At Stanford, nutrition referrals typically are made after the patient’s initial visit with a cardiologist, with the doctors, nurse practitioners, registered nurses, and RDs working together as a team. Reisenberg generally follows up with patients every two to four months in the first year and then about every six to 12 months after that. But that isn’t always the case.
“I don’t think patients are encouraged to return for dietary follow-up soon enough,” Angelone says. Nonetheless, follow-up will vary among different medical practices and clinics.
Generally, Reisenberg counsels patients to limit their saturated fat intake to no more than 6% to 7% of total calories. The rest, she says, is individualized. “We aim to help patients get to a new lifestyle that emphasizes as many whole plant foods as possible, including 3 to 4 oz of fatty, cold-water fish twice per week, and eliminates processed carbs,” she says. “I also ask my patients to include sources of mono- and polyunsaturated fats, particularly nuts (with no or limited amounts of macadamias, Brazils, and cashews due to their high saturated fatty acid content) and seeds, avocados, and olive oil.”
However, a recent review questions the American Heart Association’s stance on limiting saturated fatty acids for heart disease prevention and suggests that it’s in need of reevaluation.11 Nevertheless, Angelone asserts that counseling patients to limit saturated fats still is the best option. “Although there’s controversy as to whether decreasing saturated fat in the diet is beneficial for lowering cardiovascular disease, saturated fats are associated with elevated LDL, which, if not cleared from the blood well, can become oxidized,” she says.
As stated in the review, the debate surrounding saturated fatty acids and heart disease likely will continue. The review suggests that a food-based model may be a more meaningful clinical approach to dietary recommendations, rather than focusing on the association of a single nutrient with CHD.
In keeping with that, Angelone recommends eating foods high in antioxidants to optimize vascular health and endothelial function. She emphasizes the inclusion of specific foods that have been shown to lower inflammation, including garlic, grapes, herbs and spices, and tea.
Engaging in regular cardiovascular activity to maintain a healthy weight and promote efficient nutrient delivery to cells also is important. However, a healthy weight doesn’t always mean healthy arteries. Reisenberg emphasizes that many of her patients have normal BMIs or, if overweight, are quite active and have lots of lean body mass but still have hypercholesterolemia.
While Reisenberg prefers to customize diets to patients’ individual needs, she says if someone is looking for something more prescriptive, she’ll suggest the Mediterranean or DASH diet, both of which have been well studied. But, she says, “I believe a good diet is a good diet. Dietary intervention should be as aggressive as possible to limit the damage.”
Reisenberg points out a couple of caveats, however. First, the intensity of the intervention will depend on how far clients and patients are from following an ideal diet and how much she feels she can push them to meet that goal at any one time. Second, the degree of benefit also depends on the patient’s original diet and the number of changes made; those at the highest risk and with the least healthful diets are likely to see the most benefit. Sticking with such a strict diet can be challenging, but Reisenberg says those who have family members with FH or who died young from CHD are most likely to stick with a risk-reducing diet.
For more information on FH, visit the FH Foundation (https://thefhfoundation.org), a nonprofit organization that raises awareness of FH through education, advocacy, and research.
— Densie Webb, PhD, RD, is a freelance writer, editor, and industry consultant based in Austin, Texas.
References
1. LDL: the “bad” cholesterol. Medline Plus website. https://medlineplus.gov/ldlthebadcholesterol.html. Updated April 18, 2019; Accessed May 31, 2020.
2. Familial hypercholesterolemia. Genetics Home Reference website. https://ghr.nlm.nih.gov/condition/familial-hypercholesterolemia. Updated January 2020. Accessed May 30, 2020.
3. Gidding SS, Champagne MA, de Ferranti SD, et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation. 2015;132(22):2167-2192.
4. Familial hypercholesterolemia (FH). American Heart Association website. https://www.heart.org/en/health-topics/cholesterol/causes-of-high-cholesterol/familial-hypercholesterolemia-fh. Updated April 30, 2017. Accessed May 28, 2020.
5. Brumit ML. How common is familial hypercholesterolemia? FH Foundation website. https://thefhfoundation.org/common-familial-hypercholesterolemia. Published December 24, 2014. Accessed May 26, 2020.
6. Brumit ML. Heterozygous vs homozygous FH. FH Foundation website. https://thefhfoundation.org/heterozygous-vs-homozygous-fh. Updated May 19, 2014. Accessed May 26, 2020.
7. Akioyamen L, Genest J, Shan SD, et al. Estimating the prevalence of heterozygous familial hypercholesterolemia: a systematic review and meta-analysis. BMJ Open. 2017;7(9):e016461.
8. Khoury MJ, Thompson BL. Reducing the global public health burden of familial hypercholesterolemia: more work ahead. Centers for Disease Control and Prevention website. https://blogs.cdc.gov/genomics/2020/01/21/reducing-the-global/. Published January 21, 2020. Accessed June 2, 2020.
9. What to do when high cholesterol runs in your family. Johns Hopkins Medicine website. https://www.hopkinsmedicine.org/health/conditions-and-diseases/high-cholesterol/what-to-do-when-high-cholesterol-runs-in-your-family. Accessed May 26, 2020.
10. Humphries SE, Cooper JA, Seed M, et al. Coronary heart disease mortality in treated familial hypercholesterolaemia: update of the UK Simon Broome FH register. Atherosclerosis. 2018;274:41-46.
11. Heileson J. Dietary saturated fat and heart disease: a narrative review. Nutr Rev. 2020;78(6):474-485.