UNASSIGNED: Based on Finnish LDLR-founder variations, the prevalence of familial hypercholesterolemia (FH) in Finland is estimated to be at least 1:600. Patients with FH have increased risk of premature coronary artery disease (CAD) and thus the prevalence of FH is expected to be higher in this subgroup.
UNASSIGNED: To assess the prevalence of monogenic FH in a Finnish cohort of patients with premature CAD and elevated low-density lipoprotein cholesterol (LDL-C) levels.
UNASSIGNED: Among 28,295 patients undergoing angiography at Heart Hospital at Tampere University Hospital between 2007 and 2017, we identified 162 patients diagnosed with premature CAD (men aged <55 years and women aged <60 years) and history of high LDL-C (≥5 mmol/L) levels without secondary causes of hypercholesterolemia. Clinical probability of FH was estimated, and genetic testing of FH was carried out in 80 patients with informed consent.
UNASSIGNED: Of the 80 patients with premature CAD and history of high LDL-C levels, 70% were men; the age at diagnosis of CAD for male and female patients was 48 and 53 years, respectively. In total, 58 (73%) patients had probable (n = 54) or definite (n = 4) FH based on Dutch Lipid Clinic Network criteria. A pathogenic variant of FH was found in five (6%) patients. Prevalence of the genetically verified FH was 1:16. The FH variant was found in 75% of patients with definite FH.
UNASSIGNED: The prevalence of genetically verified FH was 1:16 among patients with premature CAD and elevated LDL-C level, which is 38 times higher than the estimated prevalence of 1:600 in the general Finnish population.

UNASSIGNED: Xanthomas are skin swellings that are caused by the accumulation of cholesterol and lipids in the body. They are associated with lipid disorders, such as familial hypercholesterolemia (FH). FH is a rare genetic disorder, which is characterized mainly by high levels of low density lipoprotein cholesterol.
UNASSIGNED: The authors report a case of an 11-year-old female who had multiple swellings all over the body with the largest measuring 7×4×3 cm in diameter. These lesions were gradually increasing in size since 4 years. She was being bullied by her school colleagues because of swellings appearance. Clinical examination revealed multiple yellowish masses on the patient\'s elbows, knees, and buttocks which were painless, firm, and nontender. Laboratory tests revealed elevated levels of serum cholesterol (512 mg/dl) and low density lipoprotein cholesterol (469.2 mg/dl). Masses ultrasound showed similar echogenicity to upper and lower extremities subcutaneous fat. Incisional biopsy microscopic images revealed clusters of foam cells. These findings led to a diagnosis of Homozygous FH and she underwent surgery to remove the xanthomas on her elbows.
UNASSIGNED: Xanthomas are small, yellowish skin swellings that form due to the presence of high lipids. As they are typically painless and small, this could lead to a late treatment or misdiagnosis. Drugs, lifestyle changes, and surgery represent treatment plan options.
UNASSIGNED: Xanthomas can be the first indication of an underlying hypercholesterolemia problem and this case report highlights the importance of early diagnosis of Homozygous FH by providing the suitable management for this case in its early stages which can prevent developing serious complication.

Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by high circulating low-density lipoprotein (LDL) cholesterol. High circulating LDL cholesterol in FH is due to dysfunctional LDL receptors, and is mainly expressed by hepatocytes. Affected patients rapidly develop atherosclerosis, potentially leading to myocardial infarction and death within the third decade of life if left untreated. Here, we introduce the disease pathogenesis and available treatment options. We highlight different possible targets of therapeutic intervention. We then review different gene therapy strategies currently under development, which may become novel therapeutic options in the future, and discuss their advantages and disadvantages. Finally, we briefly outline the potential applications of some of these strategies for the more common acquired hypercholesterolemia disease.

OBJECTIVE: Familial hypercholesterolemia (FH) is a genetic disorder marked by high LDL cholesterol and an increased premature coronary artery disease (CAD) risk. Current dichotomous classification of LDL receptor gene (LDLR) variants may inadequately capture patient variability in LDL cholesterol levels and CAD risk. This study assessed a novel approach for determining LDLR variant severity using variant-specific LDL cholesterol percentiles.
METHODS: Participants of the Dutch FH cascade screening program were screened for 456 LDLR variants. For each LDLR variant carrier, a sex- and age-specific LDL cholesterol percentile was derived from the LDL cholesterol level measured at study entry, i.e. generally from the blood drawn for DNA analysis. These percentiles were used to calculate the mean LDL cholesterol percentile for each variant. Based on the variant-specific LDL cholesterol percentiles, carriers were grouped into the following LDL cholesterol strata: <75th, 75th-88th, 88th-92nd, 92nd-96.5th, 96.5th-98th, and ≥98th percentile. Additionally, variants were categorized into class 1 (LDLR deficient) and non-class 1 (often LDLR defective) variants. CAD risk between carriers in the different LDL cholesterol strata and non-carriers was compared using a Cox proportional hazard model.
RESULTS: Out of 35,067 participants, 12,485 (36 %) LDLR variant carriers (mean age 38.0 ± 20.0 years, 47.7 % male) were identified. Carriers had a 5-fold higher CAD risk compared with non-carriers. Hazard ratios for CAD increased gradually from 2.2 (95%CI 0.97-5.0) to 12.0 (95%CI 5.5-24.8) across the LDL cholesterol strata. A 7.3-fold and 3.9-fold increased CAD risk was observed in carriers of class 1 and non-class 1 LDLR variants, respectively.
CONCLUSIONS: This study presents a refined approach for classifying LDLR variants based on their impact on LDL cholesterol levels, allowing for more precise, genotype-specific CAD risk estimation in FH patients compared with traditional methods.

Familial Hypercholesterolemia (FH) is one of the best-characterized inborn errors of metabolism, with an estimated prevalence of 1:250 in the general population. Only approximately 10% of the affected subjects are diagnosed and, therefore, under medical care, including drug therapy or, in severe cases, apheresis. Screening at the age of 6-10 years would be useful and cost-effective. There is enough evidence that children and adolescents with FH should be treated in order to reduce elevated Total cholesterol and LDL-c levels and, therefore, avoid the risk of early cardiovascular diseases. As FH was described more than 130 years ago, it is surprising that the knowledge of that very important metabolic disorder is insufficient. The present report describes clinical and pathophysiological characteristics and nutritional and medical therapies in children with familial hypercholesterolemia.

There is a gap of knowledge about the clinical and pathophysiological implications resulting from the interaction between primary hyperlipidemias and type 2 diabetes (T2D). Most of the existing evidence comes from sub-analyses of cohorts; scant information derives from randomized clinical trials. The expected clinical implications of T2D in patients with primary hyperlipidemias is an escalation of their already high cardiovascular risk. There is a need to accurately identify patients with this dual burden and to adequately prescribe lipid-lowering therapies, with the current advancements in newer therapeutic options. This review provides an update on the interactions of primary hyperlipidemias, such as familial combined hyperlipidemia, familial hypercholesterolemia, multifactorial chylomicronemia, lipoprotein (a), and type 2 diabetes.

Familial hypercholesterolemia (FH), a condition, which is characterized by a life-long exposure to markedly elevated low-density lipoprotein (LDL) concentrations from birth, and it still remains underdiagnosed and undertreated, despite the fact that its heterogeneous form represents one of the commonest genetic disorders to date. Indeed, only 10% of all estimated affected individuals have been diagnosed worldwide and for the most of them diagnosis comes too late, when atherosclerotic cardiovascular disease (ASCVD) has already been developed. Undiagnosed and undertreated FH leads to accelerated ASCVD with a high rate of premature deaths. Recently, several novel treatment modalities have been introduced, especially for the management of severe hypercholesterolemia. Nonetheless, a substantial number of FH patients still do not achieve guideline-recommended LDL cholesterol target values. In the present review we will summarize and critically discuss pitfalls and challenges in successful diagnosis and treatment of FH.

Heterozygous familial hypercholesterolemia (HeFH) patients are the prime example of subjects who are at high risk for both acute myocardial infarction (AMI) and ischemic stroke during, and post, SARS-CoV-2 infection. HeFH per se, if left untreated, results in premature clinical atherosclerosis often presenting in the fourth or fifth decade of life. The other concern in HeFH is endothelial dysfunction which is already evident from early childhood. In untreated HeFH patients, the severe hypercholesterolemia causes endothelial dysfunction from an early age, and as a result thereof, atherosclerotic lesions develop prematurely, particularly in the coronary arteries, and result in further endothelial dysfunction and inflammation in these critical segments of the arterial tree. As the pre-existing endothelial dysfunction in HeFH patients is most likely sensitive to further direct and indirect SARS-CoV-2 virus-dependent damage, we can infer that HeFH serves as an example of a comorbidity that predicts a poorer prognosis with COVID-19 infection. Indeed, a large US national database study showed that patients diagnosed with HeFH and SARS-CoV-2 infection had significantly increased Annualized Incidence Density Rates (AIDRs) of AMI when compared to matched HeFH controls not having been diagnosed with SARS-CoV-2 infection. Effective cholesterol lowering is essential for the prevention, or at least alleviation, of the detrimental effects of SARS-CoV-2 infection among HeFH patients. Due to the pre-existing subclinical or even clinical atherosclerotic cardiovascular disease in subjects with HeFH, cholesterol-lowering treatment needs to be continued or, better still, intensified during, and for an extended period post, SARS-CoV-2 infection.

Familial hypercholesterolemia (FH) is the most common monogenic disorder in humans. It affects millions of people globally, increasing the risk of developing cardiovascular disease (CVD) at a younger age due to elevated levels of low-density lipoprotein cholesterol (LDL-C) from birth. While effective traditional and novel treatments are available, the most significant challenge with FH is the lack of timely diagnosis. As a result, many patients remain undertreated leading to an increased risk of CVD. To mitigate risk, initiating early and aggressive LDL-C-lowering therapies is recommended. Moreover, given its autosomal dominant inheritance patterns, it is also recommended to perform cascade lipid and/or genetic testing of all first-degree relatives. This review highlights the importance of early FH diagnosis and available treatment options. Greater awareness and improved screening efforts can help diagnose and treat more individuals, ultimately reducing the CVD risk associated with FH.

UNASSIGNED: Many children with an FH mutation also exhibit elevated lipoprotein(a) levels, which is an independent risk factor for atherosclerotic cardiovascular disease. Studies have reported higher levels of lipoprotein(a) in adult and middle-aged women than men. There is limited knowledge on the concentration and change of lipoprotein(a) levels in children with genetic FH, and therefore we investigated sex-differences in lipoprotein(a) level and change in lipoprotein(a) in girls and boys with genetically confirmed FH.
UNASSIGNED: Medical records were reviewed retrospectively in 438 subjects with heterozygous FH that started follow-up below the age of 19 years at the Lipid Clinic, Oslo University Hospital in Norway, and of these we included 386 subjects with at least one Lp(a) measurement.
UNASSIGNED: Mean (SD) age at baseline was 13.8 (7.3) years and the age was similar between sexes. Girls had a higher lipoprotein(a) level than boys at baseline: median (25-75 percentile) 223 (108-487) vs. 154 (78-360) mg/L, respectively (p < 0.01). From baseline to follow-up measurement (mean [SD] 8.9 [6.1] years apart), the mean (95 % CI) absolute and percentage change in Lp(a) level in girls was 151.4 (54.9-247.8) mg/L and 44.8 (16.4-73.1) %, respectively, and in boys it was 66.8 (22.9-110.8) mg/L and 50.5 (8.8-92.3) %, respectively (both p > 0.05).
UNASSIGNED: We found an increase in Lp(a) levels in children with genetic FH with age, and higher levels in girls than boys, which could impact risk assessment and future ASCVD. Further research is needed to elucidate whether subjects with FH could benefit from lipoprotein(a)-lowering therapies that are under current investigations.