Dietary Approach in Familial Hypercholesterolemia

Abstract

Introduction: Familial hypercholesterolemia (FH) is a genetic disorder that remains underdiagnosed and undertreated. It is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), which leads to an increased cardiovascular disease risk. Pharmacotherapy of FH is based on high-dose statin therapy, often combined with ezetimibe and proprotein convertase subtilisin/kexin 9 inhibitors. The dietary approach is an important and supportive part of FH management. Methods: This review aimed to present the available evidence on dietary strategies in FH patients. The analyzed aspects included macronutrients such as fat and carbohydrate intake, as well as the role of dietary fiber, nutraceuticals (omega-3, beta-glucan, phytosterols, and red yeast fermented rice extract), and overall dietary models. Results and Conclusions: Based on the available data, the Mediterranean diet is a dietary model advised in cardiovascular prevention, including patients with FH. Regarding detailed recommendations, the current state of knowledge indicates dietary fat and saturated fatty acids intake limitation as an advised strategy. Supplementation of phytosterols and fiber can be also helpful in FH.

1. Familial Hypercholesterolemia

1.1. Epidemiology

Familial hypercholesterolemia (FH) is a genetic disorder that remains underrecognized and undertreated in everyday clinical practice, despite being defined sixty years ago [1]. It is generally characterized by high levels of low-density lipoprotein cholesterol (LDL-C), followed by cutaneous and/or tendon xanthomas, and often leads to an increased risk of cardiovascular diseases, e.g., coronary artery disease (CAD) [2]. FH is characterized by two main forms: heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH), indicating inheritance of genetic aberration coming from one or both parents, respectively [3]. HeFH is more common, with a prevalence of 1:200–250 people, which can be characterized by elevated LDL-C from birth; however, due to its codominant autosomal genetic transmission, it typically leads to developing CAD between 55 and 60 years [4,5]. On the other hand, HoFH can affect one patient in 160,000–320,000 people but if left untreated can lead to CAD even in childhood [4,6]. The prognosis for untreated HoFH is extremely unfavorable as most patients develop CAD and die before 30 years of age [2]. The diagnosis of FH is usually based on clinical presentation, evaluated with the Dutch Lipid Clinic Network criteria, Simon Broome register, or WHO criteria [4]. Dutch Lipid Clinic Network criteria are based on information about family history, clinical history, physical examination, LDL-C level, and DNA analysis. If possible, genetic testing is advised [4].

1.2. Genetic Background

The primary causes of FH are autosomal dominant variations; however, the background of FH is genetically highly polygenic. Affected genes are involved in cholesterol metabolism, most commonly the LDL-receptor (LDLR) gene [7,8]. Phenotypically, the receptor is less able to bind LDL-C (loss-of-function), transport it to the cell membrane, and internalize it, lowering clearance of circulating LDL-C [3]. More than 1700 different variants were identified, including point variants, large rearrangements, deletions, insertions, etc. [3]. Amino acid substitution is often pathogenic, with premature stop codons always resulting in a non-functional protein [3]. Interestingly, variants of the LDLR that affect its function are spread fairly evenly throughout the LDLR gene [3]. In the Caucasian populations, the variants of the main ligand for LDLR–apolipoprotein B-100 (coded by the APOB gene) were also reported to cause loss-of-function, resulting in FH development [2,9]. ApoB has higher concentrations in addition to LDL-C in FH patients [10]. The point variant of a single-amino acid substitution of p.Arg3500 with glutamine, tryptophane, or cysteine (p.Arg3500Gln, p.Arg3500Trp, and p.Arg3500Cys) in the LDLR-binding domain hinders the function resulting in the development of FH [3]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene variants lead to gain-of-function changes and regulation of the LDLR degradation [2]. One particular variant, p.Asp374Tyr, was associated with the disease but with unclear pathogenesis.

1.3. Treatment

FH treatment involves lifestyle modifications, such as a dietary approach, obesity prevention, physical activity introduction, and smoking avoidance, to lower LDL-C levels as soon as possible after a diagnosis has been made [11]. In HoFH, it is crucial to introduce intensive LDL-C lowering therapy as early as possible; however, it is worth noting that lifestyle guidance should also be important in HeFH as well [12]. In most of the cases, intensive pharmacotherapy is needed, but it is important that lifestyle management should be still continued after pharmacotherapy introduction [4,11].

According to the European Society of Cardiology (ESC) recommendations, treatment should be initiated with high-intensity statin therapy, in most cases in combination with ezetimibe. In FH patients, the goal is usually a >= 50% reduction in LDL-C from baseline and an LDL-C <1.4 mmol/L (<55 mg/dL) in high-risk patients [4]. On the other hand, Japan Atherosclerosis Society guidelines indicate a target level of LDL-C < 100 mg/dL in primary prevention and <70 mg/dL in secondary prevention for both HoFH and HeFH, but considering the possible difficulties in target achievement in HoFH, the aim for <50% of the LDL-C pretreatment level is also acceptable [12].

Statins are often combined with other lipid-lowering agents like ezetimibe or PCSK9 inhibitors. PCSK9 inhibitors have been shown to have significant benefits in further lowering LDL-C in patients with FH, particularly those who failed to achieve lipid targets on traditional therapies [13]. In severe cases, more aggressive therapies like LDL apheresis may be necessary, particularly in affected children [4]. Treatment of FH in children can start at a young age, usually between 6 and 10 years, with ascending doses of statins, reaching therapy goals. A Cochrane systematic review based on nine randomized clinical trials involving 1177 participants aged 4–18 reported a reduction in LDL-C and an improvement in vascular function without adverse effects on the liver and muscles. The statin treatment is an effective and generally safe lipid-lowering therapy for children with FH in the short-term observations [14]. However, it is important to prioritize dietary approaches in this group at a very young age, before pharmacotherapy introduction. In a study involving 238 children (4 to 18 years old; 47% girls), educational strategies to implement therapeutic lifestyle changes in children have been shown to lead to empowerment, better adherence, and overall metabolic improvement in children with high cholesterol levels, including those with FH [15]. Because it is an inherited condition, genetic counseling and testing for family members are recommended.

Apart from pharmacological treatment, the nutritional approach is a significant and supportive part of dyslipidemia management. As already mentioned, dietary counseling should still be continued after pharmacotherapy introduction, which was acknowledged in reimbursement recommendations of lipid-lowering drugs such as evolocumab or inclisiran [16,17]. Moreover, the paper by Roy et al. indicated that diet is an important tool for CAD prevention in HeFH, but on the other hand, qualitative data from this publication suggested that the patients’ perception of dietary approach in HeFH is useless compared to medications, while it should be highlighted that healthy diet is still the foundation of CAD prevention in HeFH [18,19]. The dietary approach is the first-line approach, as the guidelines for diagnosis and treatment of hypercholesterolemia during pediatric age from the National Cholesterol Education Program indicate that an appropriate diet should be introduced at the age of 2 years old [20]. Such a dietary approach is safe in terms of future nutritional status, growth, and development [20]. As mentioned above, pharmacotherapy is usually introduced later. The study by Kameyama et al. proved that a combination of pharmacotherapy with lomitapide with 56 weeks of dietary treatment in HoFH is successful as long as dietary education and counseling are introduced and ongoing [21]. A randomized clinical trial aimed at lifestyle improvement (physical activity, dietary intake, smoking, and compliance with statin therapy) published by Broekhuizen et al. evaluated tailored feedback influence on health improvement. Interestingly, the intervention of web-based advice was not superior to general recommendations in FH patients, stating that they are sufficient in enforcing basic statin therapy [22].

This review aimed to present the available data regarding the dietary perspective of FH management. The analyzed aspects included macronutrients such as fat, protein, and carbohydrate intake, the role of dietary fiber, nutraceuticals, and overall dietary models. PubMed, Cochrane, and Scopus databases were searched with terms such as “familial hypercholesterolemia”, “diet”, “dietary”, “nutrition”, “ketogenic”, “Mediterranean’, “fat”, “protein”, “carbohydrates”, “fiber”, “nutraceuticals”, and “diet response”, without any time restrictions. The available articles were pre-screened based on titles and abstracts.

2. Dietary Approach in FH

2.1. Fat

A meta-analysis by Barkas et al. described the effect of a cholesterol-lowering diet and other interventions on the incidence or mortality of cardiovascular disease, as well as lipid profiles in patients with FH [23]. This meta-analysis was based on 17 studies, which included 376 participants divided into eight comparison groups. The intervention time ranged from 3 to 13 weeks. There was no information on whether the studies were based on HeFH or mixed groups. Based on the results of the meta-analysis, the omega-3 fatty acid intake significantly reduced triglyceride levels compared with placebo. There was a nonsignificant trend towards a reduction in total cholesterol (p = 0.05) and LDL-C (p = 0.05). However, compared with a cholesterol-lowering diet, additional consumption of plant stanols reduced total cholesterol and LDL-C. A similar relationship was observed between plant sterols and cholesterol. It is worth noting that the individual response to omega-3 fatty acid on triglyceride levels can differ individually [24]. One of the reasons might be altered methylation levels in genes related to lipid metabolism in peripheral blood mononuclear cells [25]. Another reason might be linked to the role of the gut microbiome in reducing triglycerides with omega-3 supplementation [26]. However, despite the reduction in total cholesterol and LDL-C by plant stanol enrichment in 42 children with FH in a study by Jakulj et al., endothelial function was also assessed. The standardized protocol of flow-mediated dilation was performed in the supplied and control groups, with no significant difference between groups [27].

In a double-blind, randomized, controlled trial involving 17 participants (healthy volunteers aged 18–65 years with a body mass index (BMI) ranging from 18.5 to 27 kg/m²), saturated fatty acid (SFA) or polyunsaturated fatty acid (PUFA) products were administered in a random order for 3 days. Fasting stool and blood samples were measured before and after that 3-day intervention. Total cholesterol levels were shown to be significantly reduced by the PUFA intervention compared with SFAs, while no significant effect was found on triglycerides and free fatty acids [28].

In the study by Pimstone et al., Chinese FH heterozygotes living in Canada (n = 19) were observed and screened for LDLR variants, compared to patients living in China (n = 10) [29]. Elevated plasma LDL cholesterol levels were found to be significantly higher, by as much as ~70%, in FH heterozygotes with specific LDLR variants living in Canada compared with those living in China. This difference was attributed to dietary fat intake [30]. The diet of the Canadian FH cohort compared to the typical Chinese diet indicated a higher percentage of dietary calories (33.5 ± 9.0%). The Chinese FH cohorts consumed a typical Chinese diet, with fat constituting 20% of calories, mostly PUFA. In the Canadian cohort, consumption of a low-calorie, low-fat diet for 3 months (13% calories from fat), led to LDL-C decreasing by 21.1%. The most likely environmental factor was the nature of the diet consumed by both groups. The occurrence of significantly lower mean plasma cholesterol concentrations in rural areas of mainland China than in Western populations has been well documented, and, importantly, this is thought to correlate with a lower incidence of CAD. Further evidence that diet may have a significant effect on lipoprotein levels in FH comes from the marked reduction in LDL-C to the normal range that occurred in one FH heterozygote male from a Chinese Canadian cohort when he consumed a very low fat diet (13% fat as calories), which is comparable to the typical rural Chinese diet. A significant genetic advantage referring to that phenomenon was described in the paper by Hobbs et al. [31]. These results suggest that strict caloric restriction and reduction in dietary fat without pharmacotherapy may be sufficient to reduce cholesterol concentrations in other FH patients to the levels observed in HeFH patients living in China. A study involving a total of 205 HeFH patients (≥18 years) and 228 controls showed that HeFH patients who followed a healthy dietary regimen had higher plasma levels of omega-3 and omega-6 PUFAs and lower levels of inflammatory markers, including markers of platelet inflammation. This may suggest that adherence to an overall healthy dietary pattern may be beneficial for HeFH patients regardless of the cholesterol-lowering effect of the diet [32].

The comparison of Spanish and Norwegian FH children revealed that in the Norwegian group, fat and monounsaturated fatty acid (MUFA) intakes were directly correlated with total cholesterol, LDL-C, and ApoB and inversely correlated with high-density lipoprotein cholesterol (HDL-C) levels. In the Spanish group, the intake of fats (mainly MUFA) was directly associated with HDL-C and apolipoprotein A1 (ApoA1) levels [33]. What is more, an inverse significant association was also observed in another study of 190 adult patients with FH from Spain (n = 98) and Brazil (n = 92) between MUFAs and PUFAs and their ratio to SFAs and LDL-C and ApoB levels [34]. Another observation in 54 FH children showed that SFA intake was positively correlated with lowered plasma total cholesterol, LDL-C, and ApoB levels [35]. An extension of this approach was presented in a study involving 17 children and young adolescents (6 boys and 11 girls, aged 4 to 19 years) diagnosed with FH; dietary training (six dietary counseling sessions) and a classical low-fat/low-cholesterol diet enriched with rapeseed oil was introduced. During the first two months, participants received orally an average of 15 g/day, and for the remaining three months, an average of 22 g/day of rapeseed oil. During the five months of the rapeseed oil diet, serum triglyceride concentrations decreased by 29%, very low density lipoprotein cholesterol (VLDL-C) decreased by 27%, total cholesterol decreased by 10%, and LDL-C decreased by 7%. The results indicate that, in children and adolescents with FH, a lipid-lowering diet with rapeseed oil has an effect on serum total cholesterol and LDL-C levels and a reduction in triglycerides and VLDL-C [36]. Moreover, a randomized, double-blind pilot study involved 21 children aged 6–18 years with diagnosed FH and compared two low-fat diets enriched with MUFAs from rapeseed oil or PUFAs from sunflower oil. All visible fats were replaced by rapeseed or sunflower oil (14–27 g/day) for 13 weeks. Both fat-modified diets resulted in a significant reduction in total cholesterol by 9.4% and LDL-C by 12.7% for rapeseed oil and 11.3% for sunflower oil. However, the study suggests that rapeseed oil is likely to have more beneficial effects on the cardiovascular risk profile [37].

In a cross-over study with 19 patients with FH treated with simvastatin, 8 weeks of a low-fat diet significantly decreased total cholesterol, LDL-C, and HDL-C levels compared to a high-fat diet [38]. However, no significant differences in total cholesterol, LDL-C, HDL-C, or triglycerides were concluded in a systematic review of randomized clinical trials [39].

To conclude, dietary modifications regarding fat intake are an advised approach in FH. They should include fat intake reduction along with SFA intake limitation.

2.2. Carbohydrates

There were no available studies that analyzed the relationship between carbohydrate intake and lipid profiles in FH. However, recent comments suggest that low-carbohydrate diets should not be recommended to patients with FH [40] and do not decrease cardiovascular risk overall [41].

According to dyslipidemia management guidelines, daily carbohydrate intake should be between 45 and 55% of total daily caloric intake [4]. Dietary carbohydrates mainly affect plasma triglycerides and HDL-C levels, while having a neutral effect on total cholesterol and LDL-C levels [42]. Moreover, elevated plasma lipoprotein (a) levels are associated with an increased risk of CAD [43]. Several studies have examined the effect of a high-carbohydrate diet versus a low-carb diet on lipoprotein (a) levels. In 2010, 63 participants underwent a nutritional intervention consisting of 4 weeks of a low-carb diet and 4 weeks of a high-carbohydrate diet [44]. The study participants were healthy non-smoking men and women at least 20 years old. The low-carb diet provided 45% of energy from carbohydrates, 40% from fat (including 13.8% PUFA, 13.0% SFA, 11.0% MUFA, and 3.4% trans), and 15% from protein, while the high-carb diet provided 65% of energy from carbohydrates, 20% from fat (including 4.9% SFA, 9.9% MUFA, 5.1% PUFA, and 2.4% trans), and 15% protein. In both diets, the ratio of simple to complex carbohydrates was 50:50 between the diets. The results of this study show that compared to a low-carb diet, a high-carb diet increased lipoprotein (a) levels by 12% and lowered LDL-C levels by 7 mg/dL [44]. What is more, in 2022, the study by Ebbeling et at. showed that a low-carb diet high in SFA reduced lipoprotein (a) levels by 15% and simultaneously lowered insulin and triglyceride levels after 20 weeks of the diet compared to a high-carb diet [45]. However, it is still underlined that despite these observations, considering the potential effect on the cardiovascular risk associated with higher SFA intake, the research conducted to date is insufficient to consider the application of ketogenic diets in patients with elevated lipoprotein (a) levels [46].

2.3. Fiber

Fiber is one of the carbohydrates that is an extremely important component of the diet, as it has a positive effect on the functioning of the entire digestive system [47]. The European Food Safety Authority (EFSA) defines dietary fiber (DF) as indigestible carbohydrates and lignin [48]. Fiber consists of non-starch polysaccharides (NSPs), such as cellulose, hemicelluloses, pectins, and various hydrocolloids (gums, mucilages, and β-glucans). Dietary fiber also includes resistant oligosaccharides, such as fructooligosaccharides (FOSs) and galactooligosaccharides (GOSs), as well as resistant starch (RS), which encompasses physically trapped starch, raw starch granules, retrograded amylose, and chemically or physically modified starch. Lignin is present in fiber, associating with polysaccharides. Its regular consumption contributes to an improvement in intestinal peristalsis, which promotes efficient digestion and prevents constipation [47]. Furthermore, fiber helps lower cholesterol and blood glucose levels, which in turn reduces the risk of cardiovascular disease and type 2 diabetes [46,49]. Fiber is a dietary component that comes in two main forms: soluble and insoluble. Soluble fiber, which has the ability to dissolve in water, is mainly found in vegetables such as carrots, broccoli, onions, and artichokes, as well as fruits, legumes, and cereals such as oats and barley. Insoluble fiber, on the other hand, which does not dissolve in water, can be found mainly in cereals and whole-grain products [50,51]. According to the 2019 EAS/ESC guidelines, a daily fiber intake should aim for 25–40 g [4]. It is worth noting that, of this amount, 7–13% should be soluble fibers. For pediatric patients, the recommended daily amount of fiber is 8.4 g for every 1000 kcal consumed in the diet [52]. The positive effects of fiber on fat-related metabolic pathways are well documented. Fiber contributes to lowering plasma levels of total cholesterol and LDL-C. The evidence for this has been confirmed by the European Food Safety Authority (EFSA), which concluded that regular consumption of fiber can have a beneficial effect on the lipid profile, resulting in reduced risk of cardiovascular disease [48,53,54].

In recent decades, the consumption of organic foods has become increasingly popular, with the risk of overconsumption being low, as excessive fat intake is rare in families of FH patients [55]. On the other hand, the daily intake of whole-grain pasta, cereals, and breads often faces difficulties in acceptance [55]. In a study by Molven et al. which involved 610 children with FH aged 12–14 years, there were no significant differences in the consumption of fish, vegetables, berries, fruits, or fiber-rich grain products compared to children without FH [56]. This suggests that children with FH may be more sensitive to dietary recommendations for fat intake than those for other food groups. Consumption of fiber-rich bread and fruit, vegetables, and berries was equally high in both groups. In addition, both groups of children, with and without FH, regularly used omega-3 dietary supplements at similar rates (59% and 56%). There was only one interventional study available, which involved fiber administration in FH. The effect of 3 months of guar supplementation along with bezafibrate administration (bezafibrate alone or bezafibrate in combination with guar) in a cross-over in 12 FH patients led to an additional significant lowering of the total cholesterol associated with a significant decrease in LDL-C levels [57]. A Cochrane systematic review by Malhorta et al. indicated limited data on dietary fibers, without the possibility to definitively conclude their efficacy [39]. Additional studies are needed to investigate the efficacy of dietary fibers in a cholesterol-lowering diet in patients with FH. However, increasing the intake of soluble fiber is generally recommended in the dietary plan.

2.4. Protein

The data regarding the modulation of protein intake in terms of lipid profile in FH are very limited. The study by Gaddi et al. showed that 4 weeks of a soy diet caused a significant decrease in total cholesterol and LDL-C levels [58]. A study by Jacques et al. compared the effects of diets containing cow’s milk or a soy protein drink on plasma lipids and lipoproteins in children with FH. After a stabilization period of 6 weeks without any hypolipemic medication,10 patients aged 6–12 years were given diets containing 20% energy in the form of protein, 35% of which came from cow’s milk protein or soy protein isolate. The soy beverage, compared to cow’s milk, resulted in a significant reduction in blood triglycerides and LDL-C, as well as a significant increase in HDL-C, indicating that consumption of the soy beverage may be beneficial in the prevention of coronary heart disease in children with FH [59]. In a randomized controlled trial in pediatric patients affected by HeFH, the effect of a soy-enriched fat-modified diet compared with a fat-modified diet on LDL-C over a 13-week period was assessed. The decrease in LDL-C was statistically significantly greater in the soy group compared with the control group at week 7 and trended towards significance at week 13. This study demonstrated the efficacy and safety of dietary treatment with soy in pediatric patients affected by HeFH. The decrease in LDL-C was strongly correlated with isoflavone levels, further highlighting the beneficial effect of soy consumption [60]. Moreover, increasing dietary protein intake with the reduction in carbohydrate intake in a small study with FH patients receiving cholestyramine led to significant changes in HDL-C and the LDL-C/HDL-C ratio and triglyceride levels [61]. The positive results of these observations might be caused by the fact that the increase in protein intake is accompanied by the reduction in fat and carbohydrate intakes, which were already described as an advised approach. However, these results suggest the need for future research on this topic.

2.5. Dietary Models

At the population level, diet is one of the most important environmental factors affecting LDL-C and other cardiovascular risk factors [49,62]. Healthy eating habits are the cornerstone of the FH treatment, and it was observed that dietary habits are better in older patients with FH, but it needs to be considered that micronutrient and vitamin intake might be affected [63]. In European and North American countries, one of the main dietary attitudes is to reduce SFAs by substituting animal fats with vegetable oils [64]. As already highlighted, dietary counseling is an important part of FH treatment. From the patient’s perspective, offering a dietary model can be potentially easier to implement than following numerous detailed guidelines.

In a Spanish study with 7447 participants (55 to 80 years of age, 57% women) at high cardiovascular risk, a Mediterranean diet without energy restriction fortified with extra-virgin olive oil or nuts was contrasted with a low-fat diet. The median follow-up of 4.8 years showed that participants assigned to a Mediterranean diet without energy restrictions, complete with extra-virgin olive oil or nuts, had lower rates of major cardiovascular events than those assigned to a low-fat diet. These results confirm the beneficial effect of the Mediterranean diet on the primary prevention of cardiovascular disease [65]. Another study involving 92 participants (mean age 45 years, 58.7 percent female) and 98 individuals with FH (mean age 46.8 years, 60.2 percent female) also confirmed the association of following a Mediterranean diet with biomarkers of dyslipidemia and low inflammation in adults with molecularly confirmed FH from Brazil and Spain [66]. Greater adherence to the Mediterranean diet was shown to be associated with lower rates of dyslipidemia and less inflammation in people with FH; however, the authors did not describe the length of the follow-up [66].

According to the most recent reports, diets lower in SFAs may lower LDL-C, but their effect appears to be moderate. The Mediterranean diet has a much stronger effect on plasma LDL-C, ApoB, and high-sensitivity C-reactive protein concentrations than the SFA-restricted diet. Meanwhile, in patients with FH and excess body weight, the use of calorie-restricted diets can reduce weight and improve triglyceride levels [67].

What is more, a cross-sectional study that analyzed the impact of Nordic and Mediterranean diets on lipid profiles in 56 HeFH children showed that overall LDL-C, HDL-C, and triglycerides levels were not significantly different between these two dietary models. On the other hand, the analysis with nuclear magnetic resonance revealed that the mean size of LDL-C particles in the Mediterranean diet group was larger, while the HDL-C size was smaller than that of the Nordic diet group [68].

Interestingly, a prospective SAFEHEART study focused on the lifestyle of adult HF patients compared to non-affected relatives in general and by adherence to the Mediterranean diet [69]. It was observed that FH patients generally consumed more vegetables, olive oil, and skimmed milk, lowering the intake of SFAs and cholesterol compared to non-affected relatives, but objective SFA and sugar intake still exceeded recommendations. The awareness and change in lifestyle are considered beneficial in controlling cardiovascular disease risk compared to related and unrelated populations [69]. However, studies show that the actual nutrition of adults with FH is often not in line with international guidelines. A study involving 100 patients over 18 years of age showed an excessive intake of protein and total fat, including SFAs and cholesterol. In contrast, fiber intake was insufficient. Only 47.9% of patients declared eating vegetables daily, with 39.1 % declaring eating fruit and berries. Only 53.8% of patients regularly included fish in their meals [70]. In another study, the dietary habits of 70 Romanian patients diagnosed with FH and 20 controls were assessed using a food frequency questionnaire, a physical examination, and blood tests. The study reveals that although FH patients avoid fast food, they still have a high carbohydrate intake compared to the control group. Further studies are needed to obtain a comprehensive nutritional assessment of these patients [71]. Furthermore, the results of another study of 15 Ukrainian pediatric patients suggest a lack of complete dietary adherence in all patient age groups. FH patients aged 5–9 years consumed more fat than the recommended daily intake. There was a significant vitamin D deficiency. Children with FH aged 10–14 years consumed fewer carbohydrates and fats per day and showed deficiencies in protein, calcium, iron, iodine, zinc, and vitamin D, and FH patients aged 15–18 years had slightly increased daily cholesterol intake and vitamin D deficiency [72].

To sum up, the Mediterranean diet is one of the best-studied among the many dietary models and the most effective dietary model in a population at high cardiovascular risk. That is why it can be advised in the dietary management of FH.

3. Supplementation in FH

3.1. Plant Sterols and Stanols

Plant sterols are chemical compounds that can be described as steroidal alcohols with specific side chains distinct from cholesterol. Plant stanols, on the other hand, are 5-alpha-saturated derivatives of plant sterols. As both sterols and stanols cannot be synthesized by the human body, they must be provided with food or dietary supplements [73]. Several studies have shown that currently recommended dietary regimens for the treatment of HeFH can be optimized by including sources of plant sterols in the diet. Plant sterols, known for their blood cholesterol-lowering potential, can support traditional treatments by contributing to better lipid control. Supplementing the diet with these components may, therefore, improve the efficacy of therapy, suggesting the need to consider them in current dietary recommendations for patients with FH [39]. Dietary interventions are an important element in the management of patients with FH, especially in those who cannot start or tolerate standard lipid-lowering therapy. In children who cannot take medication and in patients who experience adverse effects associated with therapy, appropriate dietary modifications are crucial. As already mentioned, manipulation of dietary fat content, or including soy protein, may be beneficial [4].

An interventional study conducted by Becker et al. assessed the effect of plant sterol supplementation on children with FH [74]. The study involved seven children who were supplemented with sitosterol at a dose of 2 g three times a day for three months. Results showed that the dietary intervention alone lowered total cholesterol by 4.5% and LDL-C by 6.6%. However, the addition of sitosterol further improved the effects, resulting in a further 17% reduction in LDL-C [74]. Similar results of a 10.2% reduction in LDL-C and a 7.4% reduction for total cholesterol were observed in 38 children with FH [75]. Patients with the sterol ester spread not only benefited in lipid blood tests but indicated better tastiness in blind tests [75]. All the patients were following dietary recommendations, and the intake of sterol ester was 1.6 g daily. A higher dose of intervention (2.24 g/day) in 19 FH families, including 24 children (ages 3–13), 4 parents, and 16 healthy family members, reduced LDL-C by 11–20% by inhibiting cholesterol absorption regardless of the simvastatin therapy [76]. Furthermore, Guardamagna et al. conducted a 12-week study on 58 children that evaluated the effect of yogurt enriched with plant sterols on the lipid profile of children with different forms of dyslipidemia [77]. In children with FH, a 10.7% reduction in LDL-C was observed, and the yogurt was well tolerated. Additionally, Garoufi et al., in a larger study with 59 pediatric patients on a low-lipid diet, administered yogurt with 2 g of plant sterols daily, resulting in a 13% reduction in LDL-C compared to baseline values, with no effect on HDL-C, triglycerides, or plasma lipoprotein (a) [78]. A study by Gylling et al. was based on 14 children (7 boys and 7 girls) aged 9.1 ± 1.1 years (2–15 years) diagnosed with FH and involved the use of a low-fat, low-cholesterol diet for 6 weeks, which was rich in monoenoic fatty acids [79]. Cholesterol intake was 3.2 ± 0.1 mg/kg/day in both periods, and the percentage of energy in fat was 33%, 14% in the form of SFA, 12% in the form of MUFA, and 7% in the form of PUFA. The introduction of sitostanol ester margarine reduced total cholesterol, IDL, and LDL by 11%, 26%, and 15%, respectively, and increased HDL-C by 4%. Moreover, the HDL-C/LDL-C ratio changed by 27% in children with HeFH. Similar changes were also observed in adults consuming sitostanol or soluble sitostanol ester. The HDL-C/LDL-C ratio increased from 0.17 to 0.21 and from 0.23 to 0.30, respectively. A meta-analysis based on four studies was performed to determine the efficacy of phytosterols and stanols in lowering total cholesterol and LDL-C in individuals with FH [80]. The sterols were administered at doses ranging from 1.6 to 2.8 g/day. Subjects were heterozygous, aged 2 to 69 years. Spreadable fats enriched with 2.3 ± 0.5 g phytosterols/stanols per day significantly reduced total cholesterol from 7 to 11% and LDL-C with a mean decrease of 0.64 mmol/L. However, this intervention had no effect on triglycerides and HDL-C levels. A similar lack of effect was observed in a study on adult patients in a double-blind crossover trial by Neil et al. based on the 2.5 g/day phytosterol addition [81]. After 4 and 8 weeks, the LDL-C decrease was significant in the intervention group, but no significant change was observed in Apo A1 and B, HDL-C, and triglycerides levels.

To sum up, phytosterol supplementation can be considered as an addition to FH therapy.

3.2. Omega-3 Acids

Omega-3 acids belong to the PUFA group and should be a part of a balanced diet. However, additional supplementation of omega-3 can also be considered in terms of dyslipidemia treatment. In an 8-week, open-label, randomized, crossover study in 20 patients (10 women and 10 men) with FH, the effect of omega-3 fatty acid ethyl esters (omega-3FAEE) (4 g/day) on postprandial arterial elasticity after oral fat loading was tested [82]. All patients maintained their cholesterol-lowering or antihypertensive medications during the study. There were no significant changes in dietary intake or energy from fat, protein, carbohydrates, or alcohol. Omega-3FAEE significantly reduced systolic and diastolic blood pressure, fasting plasma triglycerides, ApoB, VLDL-apoB-100, and apoB-48. The sample size was relatively small but adequately powered (>90%). The data from the study suggest that treatment with omega-3FAEEs, at a dose comparable to two clinical trials (the REDUCE-IT and STRENGTH studies), improves postprandial C1 via a mechanism related to lowering plasma triglycerides and TRL-apoprotein (a).

In a double-blind, placebo-controlled crossover study involving 34 patients with FH treated with statins (mean age 46.6 years), participants were treated for 3 months with a high dose of omega-3 PUFA (2 g × 2) and 3 months of placebo (olive oil 2 g × 2), separated by a 3-month washout period [83]. The study assessed the effect of omega-3 PUFA on early atherosclerosis in patients with FH by assessing in vivo (peripheral arterial tonometry) and in vitro (plasma dimethylarginine asymmetry and E-selectin) endothelial function. The study found no changes in the reactive hyperemia index compared with the placebo. Adding omega-3 PUFA to standard lipid-lowering therapy in genetically verified patients with FH did not affect endothelial dissolution markers and their function in vivo. In a study by Hande et al., the effect of high doses of omega-3 PUFA on platelet function and inflammatory markers was analyzed in 34 patients with HeFH treated with statins. It showed that supplementation with high doses of omega-3 PUFAs had no effect on platelet function, inflammatory markers, or selected hematological parameters. In conclusion, this finding does not support omega-3 PUFA supplementation in patients with FH, but further research is needed [84].

Fourteen patients with HeFH on chronic simvastatin therapy were included in a double-blind, placebo-controlled, randomized, crossover study to assess the effect of fish oil ethyl ester (5.1 g/day) on serum lipids and lipoproteins. No significant difference was observed in total cholesterol, LDL-C, HDL-C, and triglycerides [85].

To conclude, the omega-3 supplementation is mainly advised to modify triglyceride levels with no significant effect on LDL-C levels [39].

3.3. Beta-Glucan

The role of dietary fiber was also discussed in previous paragraphs; however, similarly to omega-3 acids, it can also be additionally supplemented over typical dietary intake. Soluble fibers, such as β-glucan found in oats and barley, contribute to lowering blood lipid levels through several mechanisms. Firstly, they act as bile acid sequestrants, which causes bile acids to be excreted from the body, forcing its production from cholesterol. As a result, this leads to a reduction in total cholesterol and LDL-C levels. Furthermore, soluble fibers inhibit fatty acid synthesis, which also has a beneficial effect on the lipid profile. In addition, β-glucan can up-regulate LDL-R, which increases the uptake of LDL by the liver and contributes to further lowering cholesterol levels [86]. As a result, it leads to a reduction in triglycerides and lower total cholesterol and LDL-C levels [87]. There is no available data from studies regarding beta-glucan supplementation in the FH group. However, regarding other groups, a meta-analysis by Brown et al. involving 67 randomized controlled trials examined the effect of soluble fibers on the reduction in blood lipid levels. The results showed that intake of soluble fibers at a dose of 2 to 10 g per day led to a reduction in triglycerides by 1.25 mg/dL and LDL-C levels by 2.2 mg/dL for each gram of soluble fiber consumed [88]. In addition, another meta-analysis, involving 28 randomized controlled trials and analyzing the effect of β-glucan (over 3 g per day) on lipid profiles, also confirmed that consumption of oats, rich in β-glucan, can significantly reduce total cholesterol and LDL-C levels, while there was no significant change in HDL-C levels compared with baseline values [89].

These results indicate potential health benefits associated with an additional increase in the dietary intake of soluble fiber and β-glucan; however, studies in FH are needed to support these findings in FH.

3.4. Red Yeast Fermented Rice Extract

Red yeast rice extract (RYR), derived from the fermentation of rice by the fungus Monascus purpureus, is one of the popular nutraceuticals. It can contribute to lipid profile improvements [90]. RYR is a product containing diverse nutrients. In its composition, between 25% and 73% of sugars can be found, mainly in the form of starch. In addition, it contains between 14% and 31% protein and between 2% and 7% water. Fatty acids are also present in the composition of RYR, ranging from 1% to 5%. In addition, this rice provides sterols, isoflavones, and pigments such as rubropunctin and monascorubramine, as well as polyketides [91]. Fermentation of yeast and rice leads to the formation of a complex of substances called monacolins, which are known for their blood lipid-lowering properties. In the most commonly used dietary supplements, such as RYR, the concentration of monacolins is usually up to 1.9%. Due to these properties, monacolins may be helpful in regulating the lipid profile [92]. EFSA conducted a safety and efficacy assessment of supplements containing red yeast rice in the context of managing cholesterol levels. As a result of these studies, in 2018, EFSA published a scientific opinion that specifically addressed the use of monacolin K, the active ingredient present in RYR, in dietary supplements. The use of RYR as a dietary supplement may, therefore, be associated with a risk of human exposure to monacolin K in amounts that fall within the recommended therapeutic dose range for lovastatin of 10 to 80 mg/day [54].

Most studies on the consumption of fermented red rice in the context of hypercholesterolemia indicate the safety of its use. Conducted meta-analyses, covering 53 randomized clinical trials involving 8535 participants, aimed to assess the safety of RYR supplementation in both the short and long term [93]. The results of these studies showed no increased risk of musculoskeletal disorders, regardless of the dose of monacolin K used (≤3 mg, 3.1–5 mg, or >5 mg/day). There were also no serious health incidents requiring urgent medical intervention or hospitalization that were life-threatening or led to death. This suggests that supplementation with fermented red rice is effective and safe for patients with moderate hypercholesterolemia [93]. The International Panel of Lipid Experts has suggested that, in combination with a healthy lifestyle, the consumption of a combination of nutraceuticals with different lipid-lowering effects may be an important alternative in the prevention of CAD. This approach is particularly relevant for patients with moderate hypercholesterolemia and in cases where statin intolerance is present [94]. A study by Stefanutti et al. also showed that in HeFH patients’ intolerant to cholesterol-lowering drugs, it offers significant beneficial effects on total cholesterol, LDL-C, triglycerides, and non-HDL-C regardless of sex. It can be used as an additional approach to the strict dietary regimens in control of dyslipidemia in FH [95].

FH patients often present high levels of LDL-C, so RYR cannot be efficient enough. However, there are groups of patients who cannot tolerate or do not agree to typical pharmacotherapy, or in which RYR can be considered as an additional therapy.

The study by Guardamanga et al. included 40 HeFH children and familial combined hyperlipidemia in a randomized, double-blind, placebo-controlled trial [77]. Participants received either a placebo or a dietary supplement containing RYR extract (200 mg, equivalent to 3 mg of monacolins) and polycosanols (10 mg). After eight weeks of treatment, the results showed that the therapy was effective, safe, and well tolerated by the patients. The group that took the RYR combination achieved significant reductions in total cholesterol by 18.5%, LDL-C by 25.1%, and ApoB by 25.3%.

It is worth noting that monacolin K present in RYR used the same mechanisms as statins, so it should not be used if statin pharmacotherapy, which is often the first-line treatment in FH, is already introduced. RYR can be, therefore, advised as an addition for patients who do not tolerate or do not agree to statin therapy.

4. Other Considerations

The data referring to the impact of diet on performance in FH often come from mixed populations. It is worth noting that genetic variations can potentially impact the response to diet. The study in 67 HeFH patients, which focused on APOA4 variations, showed that after 3 months of dietary intervention, significant reductions in plasma triglyceride and very low density lipoprotein cholesterol levels were observed in APOA4-347 A/A individuals, while no changes were found in carriers of the T allele [96].

In terms of the already-mentioned soy diet, LDL-C level reduction was higher in patients with APOE e3/e3 or e3/e4 alleles, while it was not significant in e3/e2 [58].

On the other hand, the response to diet in healthy people can be attributed to APOE polymorphism, while the study in 69 HeFH patients based on 3 months of consuming a low-fat diet showed no impact of APOE polymorphism on the level of response to this dietary intervention [97]. The authors of this study suggested that genetic defects in LDL-R in FH overcome the impact of APOE polymorphism. Similarly, for APOA1-75 variations, the FH patients with a G/A polymorphism had significantly lower total and LDL-C baseline levels but their response to 3 months of a low-fat diet was similar G allele homozygotes [98].

The available data suggest that the genetic background of differences in response to dietary interventions should be further investigated in FH.

5. Conclusions

The dietary approach is an important and supportive part of FH management. The Mediterranean diet is a dietary model advised in cardiovascular prevention, including patients with FH. Regarding detailed recommendations, the current state of knowledge indicates dietary fat and SFA intake limitation as an advised strategy. Supplementation of sterols and fiber can also be helpful. More studies focused on detailed dietary strategies and their genetic background response in FH are needed.