Familial Hypercholesterolemia: Screening, diagnosis and management of pediatric and adult patients

Familial Hypercholesterolemia: Screening, diagnosis and management of pediatric and adult patients

Significant gaps in awareness of familial hypercholesterolemia among physicians in selected Asia-Pacific countries: a pilot study.

Familial hypercholesterolemia (FH) is a serious genetic disorder affecting approximately 1 in every 300 to 500 individuals and is characterised by excessively high low-density lipoprotein (LDL) cholesterol levels, substantially increased risk of early-onset coronary heart disease (CHD) and premature mortality. If FH is untreated, it leads to a greater than 50 % risk of CHD in men by the age of 50 and at least 30 % in women by the age of 60. FH can be diagnosed through genetic screening and effectively managed through pharmacological treatment and lifestyle changes. Familial hypercholesterolemia (FH) is a genetic health condition that increases the risk of cardiovascular disease. Although FH can be effectively managed with appropriate pharmacological and dietary interventions, FH detection rate through genetic screening remains low. The present study explored perceptions and experiences of FH patients (N = 18) involved in a genetic cascade screening programme. Face-to-face interviews were conducted to assess patients' knowledge and understanding of FH, explore factors linked to adherence to health-protective behaviours and examine perceptions of genetic screening. Thematic analysis of interviews revealed four themes: disease knowledge, severity of FH, lifestyle behavioural change and barriers to cascade screening and treatment. Participants recognised FH as a permanent, genetic condition that increased their risk of CHD and premature mortality. Many participants dismissed the seriousness of FH and the importance of lifestyle changes because they perceived it to be effectively managed through medication. Despite positive attitudes toward screening, many participants reported that relatives were reluctant to attend screening due to their relatives' 'fatalistic' outlook or low motivation. Participants believed that they had insufficient authority or control to persuade family members to attend screening and welcomed greater hospital assistance for contact with relatives. Findings support the adoption of direct methods of recruitment to cascade screening led by medical professionals, who were perceived as having greater authority. Other implications included the need for clinicians to provide clear information, particularly to those who are asymptomatic, related to the seriousness of FH and the necessity for adherence to medication and lifestyle changes.

The first in this series of historical reviews dealt with the pioneering animal model work of Anitschkow, implicating blood cholesterol in the pathogenesis of atherosclerosis, and the pivotally important work of Gofman, providing evidence that lipoprotein-bound cholesterol was a major factor in the human disease. This second installment reviews the early lines of evidence linking hypercholesterolemia in humans to the progression of atherosclerosis and the risk of coronary heart disease. The argument is made that by 1970, the evidence was already strong enough to justify intervention to lower blood cholesterol levels if all the available lines of evidence had been taken into account. Yet, it would be almost two decades before lowering blood cholesterol levels became a national public health goal. Some of the reasons the "cholesterol controversy" continued in the face of powerful evidence supporting intervention are discussed.

Familial hypercholesterolemia (FH) is a common autosomal dominant disease associated with premature coronary heart disease (CHD). Studies tend to show that patients with FH associated with an identified mutation (mutation+ FH) are at higher risk than patients without an identified mutation (mutation- FH). We compared the clinical and biological profile and the risk of CHD in patients with mutation+ FH and mutation- FH. In addition to LDL-C, a pathogenic mutation predicts premature CHD in FH. We successively included all patients with suspected FH (LDL-C > 190 mg/dL if age > 18 years; LDL-C > 160 mg/dL if age < 18 years) and compared patients with a pathogenic mutation with those without an identified pathogenic mutation. We studied 179 patients with mutation+ FH and 147 with mutation- FH. The mean age was 44 (± 18) years. The lipid profile was more atherogenic in those with mutation+ FH, who had higher LDL-C (254 ± 69 mg/dL vs 218 ± 35 mg/dL; P < 0.01) and lower HDL-C (53 ± 14 mg/dL vs 58 ± 17 mg/dL; P < 0.01). Despite the more atherogenic nonlipid cardiovascular profile of patients with mutation- FH, the age of CHD onset was earlier in patients with mutation+ FH (48 vs 56 years; P = 0.026). After multiple adjustment, the presence of a positive mutation was significantly associated with premature CHD (OR: 3.0, 95% CI: 1.38-6.55, P < 0.01). Patients with mutation+ FH have a more atherogenic lipid profile and a 3-fold higher risk of premature CHD, as well as earlier onset of CHD, than patients with mutation- FH.

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH.

Familial hypercholesterolemia (FH) is one of the most common genetic metabolic disorders and is associated with a high risk of premature coronary heart disease. Primary prevention directed at lifestyle changes, combined with preventive medical treatment, is the most important way to reduce the risk of coronary heart disease in individuals with FH. Knowledge about the condition and adherence to drug treatment may facilitate reaching treatment goals. The purpose of this study was to describe disease knowledge and adherence to treatment in patients with FH. Seventy-four patients, more than 18 years of age, with FH were asked to participate. A questionnaire on disease knowledge about FH and adherence to drug treatment was sent to the patients. Response rate was 92% (n = 68). Drug treatment, laboratory results, blood pressure, and smoking were also documented. Most patients knew about cholesterol, prevention, and the reason for drug treatment but were less informed about the risk of genetic transmission and family history. No significant correlation was found between knowledge and low-density lipoprotein cholesterol level. A significant, negative correlation between adherence and low-density lipoprotein cholesterol level was found (r = -.354, P < .01). Patients with FH had scant understanding about the risk of genetic transmission and family history. High adherence to drug prescription has significant correlation to low-density lipoprotein cholesterol level.

The low‐density lipoprotein (LDL) receptor mediates the specific uptake of LDL from the circulation and its intracellular degradation by a process known as the LDL receptor pathway. LDL receptor gene expression is regulated by intracellular sterol content, and is limited mainly to the liver in vivo . Mutations in LDLR , the gene encoding the LDL receptor, cause familial hypercholesterolaemia (FH), a dominantly inherited disease where accumulation of LDL in the circulation increases the risk of coronary heart disease. Defects in other genes, including APOB , encoding the ligand for the LDL receptor, ARH , encoding a protein required for its internalisation and proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), encoding a protein that reduces LDL receptor protein levels, cause a similar disorder because the encoded proteins are involved in the LDL receptor pathway. FH can readily be treated with cholesterol‐lowering drugs to reduce cardiovascular risk effectively, and identification of the causal genetic defect allows unequivocal and early diagnosis. Key Concepts: The LDL receptor mediates specific uptake and intracellular degradation of serum LDL. Inherited defects in the LDL receptor pathway cause familial hypercholesterolaemia (FH), characterised by increased serum LDL and increased risk of coronary heart disease. Most FH patients have mutations in LDLR , but defects in other genes cause a similar disorder. A recessive form of FH is caused by null mutations in ARH, a clathrin adaptor protein required for LDL receptor internalisation. A dominant form of FH is caused by gain‐of‐function mutations in PCSK9 , which encodes a protein that promotes degradation of LDL receptor protein. Dominant loss‐of‐function mutations in PCSK9 reduce serum cholesterol and risk of coronary heart disease. One relatively common dominant mutation in APOB , encoding the ligand for the LDL receptor, causes familial defective apoB (FDB). LDLR transcription is regulated by sterol response element‐binding proteins (SREBP) in a complex mechanism involving several other proteins. FH can readily be treated with cholesterol‐lowering drug therapy to abolish the increased risk of coronary disease, but is currently under‐diagnosed. Identifying causal mutations in known patients and screening their relatives should identify more affected individuals.

Introduction: During the last 30 years, treatment of familial hypercholesterolemia (FH) has been revolutionized, but it is not known if both sexes equally benefit in these advances, and whether this could have affected the sex difference in risk of coronary heart disease (CHD). We aimed to study sex difference in the risk of CHD between men and women with FH compared to non-FH men and women. Methods: We obtained data on CHD hospitalization and death from Norwegian health registries in 4,525 individuals diagnosed with FH between 1992 and 2014 and an age and sex matched control population of 88,892. The sex distribution was about 50/50 between women and men, and the mean age at start of follow-up was 36 years. Results: The cumulative incidence of CHD (FH vs. non-FH controls) in women and men are shown in Figure 1 with a clear increased risk in FH compared to controls. The cumulative incidence starts to increase at a younger age in men compared with women, both in FH and non-FH controls. This corresponds to an age adjusted 2.6-fold higher risk of CHD in men compared with women in both the FH and control population. In the FH population, men aged 20-39 years had a hazard ratio (HR) of 5.3 (95% CI: 2.6-10.9) compared with women, whereas the corresponding HR between women and men in non-FH controls was 3.7 (95% CI: 2.6-5.3). There was no significant interaction between sex and FH status, indicating that the excess risk in men was similar in FH and non-FH controls. Stratified by sex and adjusted for age, we found that both men and women with FH had a 2-fold higher risk of CHD than controls. The highest excess risk was observed in ages 20-30 years with a of HR= 4.5 (95% CI: 2.2-9.2) and a HR of= 5.5 (95%CI: 4.60-9.34) in women and men, respectively. Conclusions: The risk of CHD among individuals with FH was higher in men than in women in all age groups presented, with no differences between the FH sample and the non-FH controls. However, the relative risk in FH compared with controls was similar for both sexes.

Familial hypercholesterolemia among unselected contemporary patients presenting with first myocardial infarction: Prevalence, risk factor burden, and impact on age at presentation

Objective: Familial hypercholesterolaemia (FH) is a common autosomal dominant inherited disease, affecting 1 in 200−500 individuals worldwide. FH is characterized by elevated circulating low-density lipoprotein cholesterol (LDL-C) concentrations. Its association with increased risk of coronary heart disease (CHD) (>10-fold, compared with patients without FH) is well documented. However, the association between FH and non-CHD atherosclerotic cardiovascular disease (ASCVD) risk has been poorly documented.Methods: PubMed was searched for English language publications regarding the association between FH and carotid artery stenosis, stroke, peripheral artery disease (PAD; lower limbs and other arterial beds), aortic valve calcification (AoVC), aortic and renal artery disease, chronic kidney disease, atrial fibrillation and heart failure, from conception until 22 December 2019.Results: Despite the small number of available studies, as well as their characteristics (sample size, diagnostic criteria used, retrospective or cross-sectional design), there is evidence for a positive association between FH and stroke, PAD or AoVC. More data are needed for definitive conclusions regarding aortic and renal artery disease, chronic kidney disease, atrial fibrillation and heart failure. There is paucity of data with respect to homozygous FH. Increased lipoprotein (a) concentrations, often seen in FH patients, may also contribute to this non-CHD atherosclerotic process. A key question is whether statins or other LDL-C-lowering therapies, provide an additional reduction in the risk of these less-recognized vascular and non-vascular complications in FH patients.Conclusions: Heterozygous FH is associated with increased risk for stroke, PAD and AoVC. Clinicians should take these non-CHD ASCVD aspects into consideration for optimal management of FH patients.

Familial hypercholesterolaemia (FH) in Wales is genetically heterogeneous

Clinical Implications of New Cholesterol Guidelines

Objective To determine the efficacy of statin treatment on risk of coronary heart disease in patients with familial hypercholesterolaemia.Design Cohort study with a mean follow-up of 8.5 years.Setting 27 outpatient...

ObjectiveThe primary objective was to study the risk of acute myocardial infarction (AMI) and coronary heart disease (CHD) in patients with familial hypercholesterolaemia (FH) and compare with the risk in...