Genetic Disorder Of Lipoprotein Metabolism Research Articles

Consensus document on diagnosis and management of familial hypercholesterolemia from the Italian Society for the Study of Atherosclerosis (SISA)

AimsFamilial Hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism that causes an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Although early diagnosis and treatment of FH can significantly improve the cardiovascular prognosis, this disorder is underdiagnosed and undertreated. For these reasons the Italian Society for the Study of Atherosclerosis (SISA) assembled a Consensus Panel with the task to provide guidelines for FH diagnosis and treatment. Data synthesisOur guidelines include: i) an overview of the genetic complexity of FH and the role of candidate genes involved in LDL metabolism; ii) the prevalence of FH in the population; iii) the clinical criteria adopted for the diagnosis of FH; iv) the screening for ASCVD and the role of cardiovascular imaging techniques; v) the role of molecular diagnosis in establishing the genetic bases of the disorder; vi) the current therapeutic options in both heterozygous and homozygous FH. Treatment strategies and targets are currently based on low-density lipoprotein cholesterol (LDL-C) levels, as the prognosis of FH largely depends on the magnitude of LDL-C reduction achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment. Addition of novel medications like PCSK9 inhibitors, ANGPTL3 inhibitors or lomitapide in homozygous FH results in a further reduction of LDL-C levels. LDL apheresis is indicated in FH patients with inadequate response to cholesterol-lowering therapies. ConclusionFH is a common, treatable genetic disorder and, although our understanding of this disease has improved, many challenges still remain with regard to its identification and management.

Prevalence and outcomes of familial hypercholesterolemia in young patients undergoing coronary bypass surgery

Abstract Background Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipoprotein metabolism, with elevated low-density lipoprotein cholesterol (LDL) levels and increased risk of premature coronary disease. Appropriate management substantially reduces the risk of adverse events; however, FH is frequently under-recognised and under-treated. The prevalence of FH amongst younger patients undergoing coronary bypass surgery, as well as their clinical outcomes, has not been described. Purpose This study aimed to determine the prevalence of FH in patients undergoing coronary bypass surgery prior to age 60 years. The association of FH on attainment of LDL targets and subsequent adverse cardiovascular events was also determined. Methods A retrospective analysis of all patients undergoing coronary bypass surgery prior to the age of 60 years was conducted at an Australian tertiary hospital during the period April 2008 and July 2022. Exclusion criteria were severe renal or hepatic impairment, uncontrolled malignancy, severe inflammatory or infectious disease, or lipid data unavailable. Baseline demographics and risk factors at the time of surgery were identified by a search of the Statewide Cardiothoracic Database. Blood lipid levels (highest, pre-surgery and most recent) and clinical outcomes were obtained from digital medical records. Dutch Lipid Clinic Network Scores (DLCNS) were calculated for all patients and grouped as ‘unlikely FH’ (DLCNS <3), ‘possible FH’ (DLCNS 3 – 5), or ‘probable / definite FH’ (DLCNS ³ 6). Attainment of LDL targets (<1.8mmol/L and <1.4mmol/L) and subsequent major adverse cardiovascular events (MACE) were compared between the ‘unlikely’ and ‘probable / definite’ FH groups. Results During the study period, 683 patients underwent coronary bypass procedures prior to the age of 60. 93 were excluded, leaving a study population of 590, with a median follow up of 7.9 years [IQR 4.7, 12.1]. Baseline characteristics are outlined in table 1. 80 patients (13.6%) were classified as ‘definite/probable FH’, 249 (42.2%) as ‘possible FH’ and 261 (44.2%) ‘unlikely FH’. As observed in table 2, patients with definite/probable FH had a significantly higher prevalence of uncontrolled lipids (81.2%) and MACE (21.3%) compared to patients with unlikely FH. For MACE, this result remained statistically significant after adjusting for age, sex, smoking status, hypertension, diabetes and surgery type (elective vs urgent) - OR 2.52 [95% CI 1.0 - 6.4]. Conclusion FH is highly prevalent in young patients undergoing coronary bypass surgery. These patients are less likely to achieve LDL targets and are more likely to suffer adverse cardiovascular events in the years following surgery. Detection of these patients may improve LDL management and clinical outcomes as well as the yield of new cases through cascade testing of close relatives.Table 1:Baseline CharacteristicsTable 2:Outcomes

Pediatric Drug Development Studies for Familial Hypercholesterolemia Submitted to the US Food and Drug Administration Between 2007 and 2020.

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipoprotein metabolism that leads to an increased risk of developing atherosclerosis and coronary artery disease. Hypercholesterolemia in pediatric patients is typically due to FH. Treatment of pediatric FH is achieved through lifestyle modifications, lipid-modifying pharmacotherapy, and/or apheresis. The primary objective of this review is to describe the characteristics of clinical trials conducted in pediatric patients with FH with data submitted to the US Food and Drug Administration from 2007 to 2020. Of 10 trials with 8 products in pediatric FH submitted to the Food and Drug Administration, 1 product was studied in both the heterozygous and the homozygous phenotypes, 5 were studied for heterozygous hypercholesterolemia only, and 2 were studied for homozygous familial hypercholesterolemia only. Most of the trials included pediatric patients ≥10 years of age and older. Clinical trial characteristics including the primary efficacy end points between pediatric and adult trials were mostly identical. Many lipid-lowering drugs with novel mechanisms of action have been recently approved or are currently being studied. In summary, the drug treatment of hypercholesterolemia in pediatric patients is expanding beyond the use of statins, and now involves multiple mechanisms of action involving cholesterol metabolism. As younger pediatric patients are diagnosed and treated for heterozygous familial hypercholesterolemia and homozygous familial hypercholesterolemia, optimizing the doses of these agents and safety studies specific to younger pediatric patients will be necessary.

Diabetes is associated with an increased risk of cardiovascular disease in patients with familial hypercholesterolemia

Familial hypercholesterolemia (FH) is the most common genetic disorder of lipoprotein metabolism, affecting 1:250 individuals worldwide. This monogenic disease is associated with lifelong elevation in circulating low-density lipoprotein cholesterol and premature cardiovascular disease (CVD). In 2016, the estimated prevalence of diabetes in Canada was 9%. In the FH population, little is known about the prevalence of diabetes and its impact on CVD risk. The objectives of this study were to investigate the prevalence of diabetes among a large cohort of FH patients and to investigate the association between diabetes and CVD risk. The FH Canada registry contains data on 3740 subjects. We selected adult patients with FH according to the Dutch Lipid Clinic Network criteria. After excluding subjects with missing data, there remained 1412 patients who were included in the final analysis. The present cohort from the FH Canada database comprises a total of 73 diabetic patients (5%). The prevalence of CVD was higher in diabetic FH patients (45%) than in nondiabetics (22%) (odds ratio 2.9, 95% confidence interval 1.8-4.7, P<.0001). However, the average Montreal-FH-SCORE was also higher in the diabetic group than in the nondiabetic group (29.7 vs 21.2, respectively, P<.0001). Diabetes was no longer a significant predictor of CVD when the analysis was adjusted for the Montreal-FH-SCORE. In conclusion, diabetic FH patients represent a high-risk group for CVD risk, most likely due to the fact that diabetic subjects have many concomitant cardiometabolic risk factors.

Long-term use of a combination of atorvastatin and ezetimibe in children with homozygous familial hypercholesterolemia

Background: Homozygous familial hypercholesterolemia (HoFH) is an underdiagnosed and undertreated genetic disorder of lipoprotein metabolism associated with mortality during young age due to accelerated atherosclerosis. There is limited data on the efficacy of lipid lowering therapies in HoFH. Methods: Medical records of 3 children with HoFH who received a combination of atorvastatin and ezetimibe for a mean duration of 11.6±1.5 years were retrospectively analysed. Results: There was a significant decrease in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) from the baseline levels (mean percent change in TC, LDL-C, TG and HDL-C of 58.5%, 56.2%, 67.5% and 29.7% respectively). Conclusions: We conclude that long-term use of a combination of atorvastatin and ezetimibe significantly lowers the plasma LDL-C concentrations in patients with HoFH without causing any significant adverse effects. Ours is the first study from India on long-term use of lipid modifying drug therapy in children with HoFH.

Risk Factors Affecting the Phenotypic Expression of Heterozygous Familial Hypercholesterolemia in Pakistani Population

Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism recognized by high plasma concentrations of low-density lipoprotein cholesterol (LDL-C), tendon xanthomas, and high risk of early coronary heart disease. The phenotypic expression of FH is variable and several genetic and other risk factors contribute to such variability in clinical expression of the disease. FH is an autosomal disorder characterized by increased levels of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and tendinous xanthmata (TX). Clinical phenotype of FH has previously been shown to be associated with increased coronary heart disease (CHD) and premature death. The present study was carried out in a Pakistani population to examine the contribution of environmental factors on the expression of this disease. A detailed examination of the physical and biochemical features of the FH was performed in a cohort of 335 individuals (202 males, 133 females) from Pakistan. Our results indicate that Pakistani females with FH had high levels of TC and LDL-C as compared to Pakistani males. Overall the concentrations of high density lipoprotein cholesterol (HDL-C) were significantly lower for both sexes as compared to the controls (normal). We have also found that high cholesterol levels were associated with increased incidence of CHD in FH Pakistani population where both male and female individuals showed 69% and 31% CHD, respectively. The mean onset age for coronary symptoms was about 38 years in males as compared to 45 years in females. A greater risk of developing CHD has been linked with levels of TC along with a history of smoking in males and presence of hypertension (HTN) in females. Our results indicate that these risk factors possibly affect and contribute in the phenotypic expression of FH in Pakistani population.

Evolocumab for the treatment of homozygous familial hypercholesterolaemia

ABSTRACTIntroduction: Homozygous familial hypercholesterolaemia (HoFH) is a genetic disorder of lipoprotein metabolism characterized by minimal or absent LDL-receptor (LDLR) function, markedly elevated low density lipoprotein cholesterol (LDLC) and premature atherosclerotic cardiovascular disease. Pharmacological control of LDLC in patients with HoFH is challenging.Areas covered: Evolocumab is a fully human monoclonal antibody directed against proprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 is a serine protease predominantly secreted by hepatocytes and interferes with physiological LDLR recycling. In HoFH monthly subcutaneous evolocumab 420mg lowers LDLC by 16-23% and by 41% from baseline compared to placebo in patients with at least one LDLR allele with residual function. Individual responses to evolocumab are highly variable. Increasing the dosing frequency to once every two weeks lowers LDLC by a further 6%. Evolocumab is not effective when both LDLR alleles carry mutations without residual function. Additionally, evolocumab lowers Lp (a) by approximately 10% in patients with HoFH.Expert opinion: Evolocumab is an effective additional option for treating HoFH patients with residual LDLR function and is likely to be used routinely in the majority of patients in addition to statins and ezetimibe because of its good tolerability and safety. Many patients receiving the triple combination of a statin + evolocumab + ezetimibe will still require additional therapies such as lipoprotein apheresis, lomitapide or mipomersen to reach their LDLC target.

Variable expressivity and co-occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy.

BackgroundThe familial inherited genetic disorder of lipoprotein metabolism affects more than 10 million individuals around the world. Lebanon is one of the several endemic areas for familial hypercholesterolemia (FH) with a founder mutation in the low‐density lipoprotein cholesterol receptor (LDLR) gene, responsible for most of the cases. We have previously shown that 16% of all familial cases with hypercholesterolemia do not show genotype segregation of LDLR with the underlying phenotype.MethodsWe used Sanger sequencing to genotype 25 Lebanese families with severe FH for the gene encoding the LDLR‐associated protein (LDLRAP1), responsible for the recessive form of the disease starting with the four families that did not show any genotype‐phenotype correlation in our previous screening.ResultsWe showed that the previously reported p.Q136* variant is linked to the hypercholesterolemia phenotype in the four families. In addition, we showed a variable phenotype between families and between members of the same family. One family exhibits mutations in both LDLR and LDLRAP1 with family members showing differential phenotypes unexplained by the underlying genotypes of the two genes.ConclusionThe p.Q136* variant in LDLRAP1 is yet another founder mutation in Lebanon and coupled with the LDLR p.C681* variant explains all the genetic causes of FH in Lebanon.

Increased Mean Platelet Volume in Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism and increases the risk of premature cardiovascular diseases. In patients with FH, platelet function may be activated; however, the extent of this activation and its etiology are unclear. We aimed to evaluate the mean platelet volume (MPV), a marker of platelet activation, in patients with FH. The study group consisted of 164 patients with FH and 160 control patients. Controls were matched for age, gender, hypertension, and smoking. The MPV was significantly higher in patients with FH than in controls (9.2 ± 0.4 vs 7.9 ± 0.6 fL, respectively; P < .001). Platelet count was significantly lower among patients with FH when compared to control patients (259 ± 51 vs 272 ± 56 × 10(3)/L, respectively; P = .03). In linear regression analysis, MPV was independently associated only with total cholesterol (β = .6, 95% confidence interval: 0.004-0.008, P < .001). We have shown that MPV was increased in patients with FH and that it was independently associated with total cholesterol level.

Familial hypercholesterolemia: A review.

Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism resulting in elevated serum low-density lipoprotein (LDL) cholesterol levels leading to increased risk for premature cardiovascular diseases (CVDs). The diagnosis of this condition is based on clinical features, family history, and elevated LDL-cholesterol levels aided more recently by genetic testing. As the atherosclerotic burden is dependent on the degree and duration of exposure to raised LDL-cholesterol levels, early diagnosis and initiation of treatment is paramount. Statins are presently the mainstay in the management of these patients, although newer drugs, LDL apheresis, and other investigational therapies may play a role in certain subsets of FH, which are challenging to treat. Together these novel treatments have notably improved the prognosis of FH, especially that of the heterozygous patients. Despite these achievements, a majority of children fail to attain targeted lipid goals owing to persistent shortcomings in diagnosis, monitoring, and treatment. This review aims to highlight the screening, diagnosis, goals of therapy, and management options in patients with FH.

The genetic basis of familial hypercholesterolemia: inheritance, linkage, and mutations.

Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism characterized by high plasma concentrations of low-density lipoprotein cholesterol (LDLc), tendon xanthomas, and increased risk of premature coronary heart disease. FH is one of the most common inherited disorders; there are 10,000,000 people with FH worldwide, mainly heterozygotes. The most common FH cause is mutations along the entire gene that encode for LDL receptor (LDLR) protein, but it has been also described that mutations in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 genes produce this phenotype. About 17%-33% of patients with a clinical diagnosis of monogenic hypercholesterolemia do not harbor any genetic cause in the known loci. Because FH has been considered as a public health problem, it is very important for an early diagnosis and treatment. Recent studies have demonstrated the influence of the LDLR mutation type in the FH phenotype, associating a more severe clinical phenotype and worse advanced carotid artherosclerosis in patients with null than those with receptor-defective mutations. Since 2004, a molecular FH diagnosis based on a genetic diagnostic platform (Lipochip(®); Progenika-Biopharma, Derio, Spain) has been developed. This analysis completes the adequate clinical diagnosis made by physicians. Our group has recently proposed new FH guidelines with the intention to facilitate the FH diagnosis. The treatment for this disease is based on the benefit of lowering LDLc and a healthy lifestyle. Actually, drug therapy is focused on using statins and combined therapy with ezetimibe and statins. This review highlights the recent progress made in genetics, diagnosis, and treatment for FH.

Guidelines applied in practice in medicare patients with acute myocardial infarction

Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism characterized by very high plasma concentrations of low density lipoprotein cholesterol (LDLc), tendon xanthomas and increased risk of premature coronary heart disease (CHD). FH is a public health problem throughout the world. There are 10,000,000 people with FH worldwide, mainly heterozygotes, and approximately 85% of males and 50% of females with FH will suffer a coronary event before 65 years old if appropriate preventive efforts are not implemented. Early identification of persons with FH and their relatives, and the early start of treatment are essential issues in the prevention of premature cardiovascular disease (CVD) and death in this population. However, guidelines for the general population formally exclude FH from their diagnostic and treatment recommendations. These guidelines have been elaborated by a group of international experts with the intention to answer the main questions about heterozygous FH (heFH) subjects that physicians worldwide face in the diagnosis and management of these patients.

Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism characterized by very high plasma concentrations of low density lipoprotein cholesterol (LDLc), tendon xanthomas and increased risk of premature coronary heart disease (CHD). FH is a public health problem throughout the world. There are 10,000,000 people with FH worldwide, mainly heterozygotes, and approximately 85% of males and 50% of females with FH will suffer a coronary event before 65 years old if appropriate preventive efforts are not implemented. Early identification of persons with FH and their relatives, and the early start of treatment are essential issues in the prevention of premature cardiovascular disease (CVD) and death in this population. However, guidelines for the general population formally exclude FH from their diagnostic and treatment recommendations. These guidelines have been elaborated by a group of international experts with the intention to answer the main questions about heterozygous FH (heFH) subjects that physicians worldwide face in the diagnosis and management of these patients.

Heme oxygenase-carbon monoxide signalling pathway in atherosclerosis: anti-atherogenic actions of bilirubin and carbon monoxide?

Atherosclerosis is a major contributor to cardiovascular disease, and genetic disorders of lipoprotein metabolism are recognized risk factors in atherogenesis. The gaseous monoxides nitric oxide (NO) and carbon monoxide (CO), generated within the blood vessel wall, have been identified as important cellular messengers involved in the regulation of vascular smooth muscle tone. Microsomal heme oxygenases degrade heme to biliverdin and CO, and the cytosolic enzyme biliverdin reductase then catalyzes reduction of biliverdin to bilirubin, both powerful chain-breaking antioxidants. Two principal isozymes of heme oxygenase have been identified, a constitutive isoform HO-2 (M(r) approximately 34,000) and an inducible isoform HO-1 (M(r) approximately 32,000), which is expressed at a low basal level in vascular endothelial and smooth muscle cells and is induced by heavy metals, oxidative stress, inflammatory mediators and oxidized low density lipoproteins. Although NO and CO modulate intracellular cGMP levels, platelet aggregation and smooth muscle relaxation, CO has a much lower affinity for soluble guanylyl cyclase than NO. Decreased production or sensitivity to NO in atherosclerosis may be compensated for by an induction of HO-1, with bilirubin acting as a cellular antioxidant and CO as a vasodilator. This review examines the evidence that oxidized low density lipoproteins (LDL), hypoxia and pro-inflammatory cytokines induce HO-1 expression and activity in vascular endothelial and smooth muscle cells, and evaluates the anti-atherogenic potential of the heme oxygenase signalling pathway.

Recent insights into the pathogenesis of type III hyperlipoproteinemia

Type III hyperlipoproteinemia is a genetic disorder of lipoprotein metabolism characterized by high plasma cholesterol and triglycerides, the presence of a characteristic lipoprotein termed β-very low density lipoprotein (gb-VLDL), xanthomatosis, and premature atherosclerosis. Defects in the gene for apolipoprotein (apo) E represent the molecular cause of this disorder. ApoE serves as a ligand for the receptor-mediated clearance of the triglyceride-rich lipoproteins from the circulation. All defects in apoE cause impaired lipoprotein clearance through the same mechanism, that is, the disruption, either direct or indirect, of the receptor-binding region of the apoE molecule. However, the receptor-binding defect alone does not fully explain the pathogenesis of β-VLDL formation, the development of type III hyperlipoproteinemia, and its mode of inheritance, which can be either recessive or dominant, depending on the apoE mutation. Recent studies suggest that other functional properties of apoE might play a role in the formation of β-VLDL. Modulation of the receptor-binding defect, association with VLDL, heparin-binding affinity, and interaction with lipolytic enzymes could all contribute to the expression of the disease phenotype and determine its mode of inheritance.