Two Cases of Sitosterolemia Falsely Diagnosed as Familial Hypercholesterolemia: Could Digging Deeper Have Avoided Harm?

Sitosterolemia is a rare monogenic lipid disease characterized by the excessive uptake of phytosterols and their accumulation in blood and tissues. Clinically, it can present with hypercholesterolemia and xanthomas, often causing it to be misdiagnosed as familial hypercholesterolemia (FH). The diagnosis of sitosterolemia can easily be confirmed and distinguished from FH with a sterol profile and genetic investigations. Here, we report a sibship of 2 sisters with sitosterolemia initially misdiagnosed as FH. This case report illustrates the importance of considering rare conditions, such as sitosterolemia, as a differential diagnosis in patients with hypercholesterolemia, xanthomas, and hematologic anomalies. It also emphasizes the underdiagnosis of sitosterolemia and the benefits of using sterol profiles and genetic testing in the diagnostic process to initiate the appropriate therapy and avoid harm to patients.

Influence of Polygenic Background on the Clinical Presentation of Familial Hypercholesterolemia.

BACKGROUND: Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH. METHODS: We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease. RESULTS: Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease is higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing variant. CONCLUSIONS: Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH.

Prevalence of Dysbetalipoproteinemia in the UK Biobank According to Different Diagnostic Criteria.

CONTEXT: Dysbetalipoproteinemia (DBL) is a multifactorial disorder that disrupts the normal metabolism of remnant lipoproteins, causing increased risk of cardiovascular disease. However, establishing a proper diagnosis is difficult and the true prevalence of the disease in the general population remains unknown. OBJECTIVE: The objectives were to study the prevalence of the disease and to validate the performance of different clinical diagnostic criteria in a large population-based cohort. METHODS: This study included 453 437 participants from the UK Biobank. DBL was established in participants having an ε2ε2 genotype with mixed dyslipidemia or lipid-lowering therapy use (n=964). The different diagnostic criteria for DBL were applied in individuals without lipid-lowering medication (n=370 039, n=534 DBL), to compare their performance. RESULTS: Overall, 0.6% of participants had an ε2ε2 genotype, of which 36% were classified as DBL, for a disease prevalence of 0.2% (1:469). The prevalence of DBL was similar between the different genetic ancestries (≤0.2%). Several diagnostic criteria showed good sensitivity for the diagnosis of DBL (>90%), but they suffered from a very low positive predictive value (0.6%-15.4%). CONCLUSION: This study reported for the first time the prevalence of DBL in the UK Biobank according to genetic ancestry. Furthermore, we provided the first external validation of different diagnostic criteria for DBL in a large population-based cohort and highlighted the fact that these criteria should not be used to diagnose DBL alone but should rather be used as a first screening step to determine which individuals may benefit from genetic testing to confirm the diagnosis.

Advances in familial hypercholesterolemia.

Familial hypercholesterolemia (FH), a semi-dominant genetic disease affecting more than 25 million people worldwide, is associated with severe hypercholesterolemia and premature atherosclerotic cardiovascular disease. Over the last decade, advances in data analysis, screening, diagnosis and cardiovascular risk stratification has significantly improved our ability to deliver precision medicine for these patients. Furthermore, recent updates on guideline recommendations and new therapeutic approaches have also proven to be highly beneficial. It is anticipated that both ongoing and upcoming clinical trials will offer further insights for the care and treatment of FH patients.

Acute pancreatitis risk in multifactorial chylomicronemia syndrome depends on the molecular cause of severe hypertriglyceridemia.

BACKGROUND AND AIMS: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis (AP). Severe hyperTG is mainly polygenic in nature, either caused by the presence of heterozygous pathogenic variants (PVs) in TG-related metabolism genes or by accumulation of common variants in hyperTG susceptibility genes. This study aims to determine if the risk of AP is similar amongst MCS patients with different molecular causes of severe hyperTG. METHODS: This study included 114 MCS patients who underwent genetic testing for PVs in TG-related metabolism genes and 16 single nucleotide polymorphisms (SNPs) in hyperTG susceptibility genes. A weighted TG-polygenic risk score (TG-PRS) was calculated. A TG-PRS score ≥ 90th percentile was used to define a high TG-PRS. RESULTS: Overall, 66.7% of patients had severe hyperTG of polygenic origin. MCS patients with only a PV and those with both a PV and high TG-PRS were more prone to have maximal TG concentration ≥ 40 mmol/L (OR 5.33 (1.55-18.36); p = 0.008 and OR 5.33 (1.28-22.25); p = 0.02), as well as higher prevalence of AP (OR 3.64 (0.89-14.92); p = 0.07 and OR 11.90 (2.54-55.85); p = 0.002) compared to MCS patients with high TG-PRS alone. CONCLUSIONS: This is the first study to show that MCS caused by a high TG-PRS and a PV is associated with higher risk of AP, similar to what is seen in the monogenic form of severe hyperTG. This suggests that determining the molecular cause of severe hyperTG could be useful to stratify the risk of pancreatitis in MCS.

Pancreatitis polygenic risk score is associated with acute pancreatitis in multifactorial chylomicronemia syndrome.

BACKGROUND: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia associated with an increased risk of acute pancreatitis (AP). The risk of AP is heterogenous and is associated with increased level of triglycerides (TG) and presence of rare variants in TG metabolism-related genes. OBJECTIVE: To determine if the accumulation of common variants in pancreatitis susceptibility genes, measured with a weighted polygenic risk score (PRS), is associated with AP in MCS patients. METHODS: A total of 114 patients with MCS underwent genetic testing for eight single nucleotide polymorphisms (SNPs) in known pancreatitis susceptibility genes (ABCG8, CLDN2, CTRB1/2, CTRC, PRSS1, PRSS2, SPINK1 and TWIST2). A weighted PRS was calculated to account for the phenotypic effect of each SNP locus. RESULTS: A high pancreatitis-PRS score (≥ 0.44) was associated with a 2.94-fold increase risk of AP (p = 0.02) among patients with MCS. MCS patients with a high pancreatitis-PRS and a rare variant in TG metabolism-related gene have a 9.50-fold increase risk of acute pancreatitis (p = 0.001), compared to those with a low-PRS and no rare variant. A multivariate analysis including the presence of rare variants, the maximal TG values and a high pancreatitis-PRS explained 26% of the variability in AP in MCS patients. CONCLUSION: This study shows for the first time that the accumulation of common variants in pancreatitis susceptibility genes is associated with AP in MCS patients. Pancreatitis-PRS could help clinicians to identify MCS patients who may be at higher risk of AP and who may benefit from more aggressive treatment.

High hsCRP concentration is associated with acute pancreatitis in multifactorial chylomicronemia syndrome.

BACKGROUND: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis (AP). However, the risk of AP is very heterogenous in MCS. Previous studies suggested that inflammation might promote disease progression in hyperTG-induced AP. OBJECTIVE: To determine if low-grade inflammation is associated with AP in MCS. METHODS: This study included 102 subjects with MCS for which high-sensitivity C-reactive protein (hsCRP) concentration was measured at their first visit at the Montreal Clinical Research Institute. RESULTS: MCS subjects with a previous history of AP had a significant higher hsCRP concentration (4.62 mg/L vs. 2.61 mg/L; p=0.003) and high hsCRP concentration (≥3mg/L) was independently associated with AP prevalence (p<0.05). Up to 64% of the variability in AP prevalence was explained by the maximal TG concentration, hsCRP concentration, the presence of rare variants in TG-related genes, and fructose intake based on a stepwise multivariate regression model (p<0.0001). CONCLUSION: This retrospective study showed for the first time that hsCRP concentration is strongly associated with AP prevalence in MCS. It also suggests that low-grade inflammation may be a driver of AP in severe hypertriglyceridemia. Prospective studies could help determine the causality of this association and assess whether medication known to reduce low-grade inflammation could help prevent AP in individuals with severe hypertriglyceridemia.

Sex differences in the presentation, treatment and outcomes of patients with homozygous familial hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal semi-dominant lipid metabolism disorder characterized by extremely high low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease. The objective of this study was to investigate sex-differences in the treatment and outcomes of patients with HoFH. METHODS: We examined clinical characteristics, lipid-lowering therapy (LLT), and cardiovascular events using descriptive statistics of patients in the Canadian HoFH registry. Major adverse cardiovascular events (MACE) were defined as the composite of cardiovascular death, non-fatal myocardial infarction, and stroke. Sex differences between continuous and categorical variables were analyzed using Mann-Whitney U test and Fisher's Exact test, respectively. RESULTS: This study included 48 patients (27 (56%) female). The median age at diagnosis in females was 14.0 (interquartile range (IQR) 9.0-30.0) and in males was 8.0 (IQR 2.0-23.0) (p = 0.07). Baseline clinical characteristics were comparable between both sexes. The median baseline LDL-C was 12.7 mmol/L (10.0-18.3) in females and 15.3 (10.5-20.0) in males (p = 0.51). Follow up LDL-C levels were 7.6 mmol/L (IQR 4.8-11.0) in females and 6.3 (IQR 4.6-7.5) in males (p = 0.1). Most patients were taking 3 or more LLTs, with comparable proportions in both sexes (p = 0.26). Apheresis was similar in both sexes, 14 (51.8%) vs. 10 (47.6%) (p = 0.2). Over a mean of 10 years of follow-up, MACE occurred in 3 females (11.1%) and 4 males (19.1%) (p = 0.2). CONCLUSION: Lipid levels and treatment were similar between sexes. MACE occurred in similar proportions between sexes, indicating that HoFH offsets the inherently lower cardiovascular risk in pre-menopausal females. Further investigation into sex-differences in HoFH in larger sample sizes is warranted.

The 20-Year Diagnostic Odyssey of a Milder Form of Cerebrotendinous Xanthomatosis.

Tendinous xanthomas are usually a sign of genetic dyslipidemias and are said to be pathognomonic for familial hypercholesterolemia. However, the differential diagnosis must also include rarer forms of genetic dyslipidemias such as cerebrotendinous xanthomatosis (CTX). In this report, we present the diagnostic odyssey of a French-Canadian patient presenting with Achilles tendon xanthomas and an unusual mild to moderate hypercholesterolemia. Comprehensive biochemical and genetic investigations confirmed the diagnosis of CTX, 20 years after the onset of her first symptoms. We also describe a new variant in the CYP27A1 gene associated with this atypical case and expand the clinical phenotype of this rare genetic condition. CTX is thought to be underdiagnosed, and early diagnosis and treatment of this disease is essential as it has been shown to greatly improve the patient's symptoms and prognosis.

Increased FH-Risk-Score and Diabetes Are Cardiovascular Risk Equivalents in Heterozygous Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic condition causing premature atherosclerotic cardiovascular disease (ASCVD). It is well established that patients with FH should be treated with statin therapy. However, there exists discordance concerning low-density lipoprotein cholesterol-lowering goals in the management of these patients between different guidelines worldwide. The objective was to compare the 10-year ASCVD risk of different subgroups of patients with and without FH including those with diabetes or a history of ASCVD and patients with FH within different FH-Risk-Score categories. METHODS: This multinational observational study used data from 3 different prospective cohorts. A total of 3383 FH and 6917 non-FH controls matched for age and sex were included (104 363 person-years of follow-up). The 10-year incident ASCVD risk was assessed using Kaplan-Meier estimates, whereas the relative risk was estimated using Cox proportional hazards regression models. RESULTS: FH patients with a high (score >20%) FH-Risk-Score (hazard ratio, 8.45 [95% CI, 6.69-10.67]; P<0.0001), FH patients with diabetes (hazard ratio, 7.67 [95% CI, 4.82-12.21]; P<0.0001), and non-FH patients with ASCVD (hazard ratio, 6.78 [95% CI, 5.45-8.42]; P<0.0001) had a significantly higher incident ASCVD risk over 10 years than the reference group (non-FH without ASCVD or diabetes). The observed 10-year risks in these groups were 32.1%, 30.8%, 30.0%, and 5.1%, respectively. The 10-year ASCVD risk associated with both FH and ASCVD was extremely high (observed risk of 50.7%; hazard ratio, 14.53 [95% CI, 12.14-17.38]; P<0.0001). CONCLUSIONS: This study strongly suggests that the observed risk of FH patients with diabetes, history of ASCVD, and FH-Risk-Score >20% is as high or higher than non-FH individuals with a history of ASCVD. More aggressive management should be recommended for these patients.

Treatment target achievement in patients with familial hypercholesterolemia: A real-world descriptive study.

BACKGROUND: Statin and ezetimibe represent the first line of lipid-lowering therapy in patients with familial hypercholesterolemia (FH), a disease associated with a strong cardiovascular risk. The current low-density lipoprotein cholesterol (LDL-C) target achievement rate in a real-world context using these conventional treatments has never been investigated in the Province of Quebec (Canada). OBJECTIVE: The primary objective of this study was to evaluate the proportion of FH patients in primary cardiovascular prevention who attained their recommended LDL-C threshold without being treated with a PCSK9 inhibitor. METHODS: Patients included in this retrospective study were followed at the Lipid Clinic of the Montreal Clinical Research Institute. All patients were molecularly defined (97%) or had a definite clinical diagnosis of FH. RESULTS: A total of 225 patients were included in this study, of which 73% were on high-intensity statin therapy. While two-thirds of the cohort achieved the LDL-C treatment target of ≥ 50% reduction from baseline, only one third attained the target of < 2.5  mmol/L (<97 mg/dL). However, patients on high-intensity statin therapy were two times more likely to achieve the < 2.5  mmol/L targets as compared to those treated with low or moderate statin intensity (p = 0.01). There was no significant difference in treatment target achievement between men and women. CONCLUSION: Target achievement rate was unacceptably low in our FH patients. Conventional lipid-lowering treatments alone may not be sufficient in most FH patients to ensure adequate cardiovascular prevention.

Validation of the Fatty Liver Index for identifying non-alcoholic fatty liver disease in a Kenyan population.

BACKGROUND AND AIM: Fatty Liver Index (FLI) is a simple clinical scoring system estimating non-alcoholic fatty liver disease (NAFLD). It is validated in European-descent and Asian populations, but not in sub-Saharan Africans. The aim of this study is to evaluate the validity of the FLI for predicting NAFLD in a population from Kenya. METHODS: Participants were recruited from a community-based study conducted in Kenya. NAFLD was diagnosed using hepatic ultrasonography. Clinical, anthropometrical, biochemical and lifestyle data were obtained. The accuracy and cut-off point of the FLI to detect NAFLD were evaluated by area under the receiver operator characteristic curve and the maximum Youden index analysis. RESULTS: A total of 640 participants (94 with NAFLD) were included. Mean age was 37.4 ± 0.4 years and 58.7% were women. Mean body mass index (BMI) was 22.3 ± 0.2 kg/m2 and waist circumference (WC) 79.1 ± 0.4 cm. A total of 15 (2.3%) participants were diagnosed with type 2 diabetes and 65 (10.2%) with obesity (BMI ≥ 30 kg/m2 ). AUROC of FLI for predicting NAFLD was 0.80 (95% CI 0.74-0.85), which was significantly higher compared to individual components gamma-glutamyl transferase and triglycerides (p < 0.05), but not compared to anthropometric parameters BMI (AUROC of 0.83, 95% CI 0.79-0.88) and WC (AUROC of 0.81, 95% CI 0.76-0.87). CONCLUSIONS: FLI is a simple valid scoring system to use in rural and urban Kenyan adults. However, this index might not be superior to BMI or WC to predict NAFLD, and those measurements might therefore be more appropriate in limited settings.

Dietary recommendations for dysbetalipoproteinemia: A need for better evidence.

The increased risk of cardiovascular disease in patients with dysbetalipoproteinemia (DBL) is well documented and is associated with the dysfunctional metabolism of remnant lipoproteins. Although these patients are known to respond well to lipid-lowering medication including statins and fibrates, the best dietary approach to lower remnant lipoprotein accumulation and to prevent cardiovascular outcomes remain unclear. Indeed, current evidence is based on studies published mainly in the 1970s, which comprise small sample sizes and methodological limitations. This review aims to summarize nutritional studies performed in DBL patients to date and to discuss potential avenues in this field and future areas of research.

Non-alcoholic fatty liver disease in patients with chylomicronemia syndromes.

BACKGROUND: Chylomicronemia syndrome is a form of severe hypertriglyceridemia (HTG) caused by the familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS). Non-alcoholic fatty liver disease (NAFLD) has been associated with components of the metabolic syndrome and is more prevalent in subjects with elevated triglycerides. OBJECTIVE: The primary objective was to compare the prevalence of hepatic steatosis assessed by conventional imaging between HTG groups (FSC, MCS and moderate HTG (mHTG)). The secondary objective was to determine the difference in the prevalence of liver fibrosis. METHODS: This cross-sectional observational study was performed on adult patients from the lipid clinic of the Montreal Clinical Research Institute (IRCM). We retrospectively reviewed the imaging reports available in the patients' files for signs of NAFLD. We also used the FIB-4 index as a surrogate marker of liver fibrosis. RESULTS: We reviewed the medical files of 300 patients; 22 with FCS, 82 with MCS and 196 with mHTG. There was significantly more hepatic steatosis in the MCS group compared to the mHTG and FCS groups (79%, 66% and 43% respectively p=0.02). There was a significantly higher prevalence of subjects within the "unlikely fibrosis" category in the mHTG group (91%) compared to the MCS (84%) and FCS groups (59%), p=0.0004. CONCLUSION: We found that the prevalence of hepatic steatosis was 3-, 2.5-, and 2-fold higher in MCS, mHTG and FCS patients than in the general population. This suggests that patients with elevated triglycerides, regardless of the underlying etiology, are at higher risk of hepatic steatosis and NAFLD.

Metabolic syndrome predicts cardiovascular risk and mortality in familial hypercholesterolemia.

BACKGROUND: The association between familial hypercholesterolemia (FH) and premature atherosclerotic cardiovascular disease (ASCVD) is well established. Several risk factors other than the cumulative low-density lipoprotein cholesterol (LDL-C) have been shown to modulate the severity of the phenotype in these patients. However, the effect of the metabolic syndrome (MetS) on ASCVD risk in FH remains to be determined. OBJECTIVES: The objective was to study the association between the presence of MetS and the incidence of different ASCVD endpoints and all-cause mortality. METHODS: This prospective follow up study used data from 5 independent FH cohorts from Europe and North America. We analysed data of 2401 adult heterozygous FH without history of a prior ASCVD event (21,139 person-years of follow-up). Multivariate Cox proportional hazards regression was used to estimate the association between MetS and the incidence of the different endpoints. RESULTS: The prevalence of MetS was 14% in the study population. The presence of MetS was a significant predictor of incident 10-year ASCVD after adjustment for traditional cardiovascular risk factors (HR 2.07, 95% CI 1.34-3.19), as well as of 10-year major adverse cardiovascular event (MACE) (HR 4.59, 95% CI 2.27-9.30), 10-year myocardial infarction (MI) (HR 4.29, 95% CI 1.91-9.63), and 30-year all-cause mortality (HR 4.87, 95% CI 1.99-11.89). CONCLUSION: Our findings suggests that FH patients with MetS, have an increased cardiovascular risk that is independent from LDL-C and other traditional risk factors. Future studies are required to determine the most appropriate strategy to reduce the cardiovascular burden associated with MetS in this population.

Sex differences in LDL-C response to PCSK9 inhibitors: A real world experience.

BACKGROUND: Previous studies have shown the efficacy of PCSK9 inhibitors (PCSK9i) in lowering LDL-C. One clinical trial with alirocumab suggested that the LDL-C reduction effect is larger in men than women. In contrast, none of the studies with evolocumab have observed a difference in the treatment effect between men and women. However, sex differences data from real life experience is lacking. In addition, the difference in LDL-C response to PCSK9i between pre- and post-menopausal women has not been investigated so far. OBJECTIVES: To compare the relative change in LDL-C following the introduction of a PCSK9i in a real-life clinical setting according to sex and menopausal status. METHODS: All patients were recruited at the IRCM lipid clinic. Lipid profiles before and after the introduction of PCSK9i were available in the medical file for 259 patients (160 men and 99 women (72 post-menopausal, 20 pre-menopausal and 7 unknown menopausal status). RESULTS: We observed a significant difference in relative LDL-C change between men (-70%) and women (-59%), p<0.0001. However, no difference was observed between pre-menopausal (-58%) and post-menopausal (-58%) women. In a linear regression model, sex remains a significant predictor of the response to PCSK9i after correction for confounding factors such as statin intensity (beta coefficient=-0.245, p<0.0001). CONCLUSION: We observed a greater relative LDL-C response to PCSK9i in men than in women in a real-life clinical context. However, it is still unknown whether this difference in LDL-C change between men and women translates into a meaningful difference on long-term cardiovascular risk.

Dysbetalipoproteinemia Is Associated With Increased Risk of Coronary and Peripheral Vascular Disease.

CONTEXT: Dysbetalipoproteinemia (DBL) is a disorder in which remnant lipoproteins accumulate in the plasma due to a genetic apolipoprotein E dysfunction in conjunction with the presence of secondary metabolic factors. An increased risk of both coronary and peripheral vascular disease (PVD) has been observed in these patients in retrospective studies. OBJECTIVE: The primary objective was to compare the incidence of atherosclerotic cardiovascular disease (ASCVD) and PVD in a cohort of patients with DBL compared with normolipidemic controls. As a secondary objective, the incidence of ASCVD and PVD was compared between patients with DBL and patients with familial hypercholesterolemia (FH). METHODS: A total of 221 patients with DBL, 725 patients with FH, and 1481 normolipidemic controls were included in the study. The data were obtained by review of medical records. RESULTS: In patients with DBL, there was an overall excess risk of PVD (hazard ratio [HR] 13.58, 95% CI 4.76-38.75) and ASCVD (HR 3.55, 95% CI 2.17-5.83) (P < .0001) when compared with normolipidemic controls. When compared with patients with FH, an increased risk of PVD (HR 3.89, 95% CI 1.20-12.55, P = .02) was observed in patients with DBL. CONCLUSION: We demonstrated that the risks of ASCVD and PVD in DBL are >3-fold and >13-fold higher, respectively, than normolipidemic controls. Furthermore, the risk of PVD is ∼4-fold higher in DBL than in FH. Adequate screening of DBL is imperative to improve the clinical care of these patients by preventing the development of ASCVD.

Effect of the LDL receptor mutation type on incident major adverse cardiovascular events in familial hypercholesterolaemia.

AIMS: Patients with familial hypercholesterolaemia (FH) are at increased risk of cardiovascular disease (CVD) due to extremely high circulating LDL cholesterol (LDL-C) concentrations. Our objective was to study the effect of the type of LDL receptor (LDLR) mutation on the incidence of major adverse cardiovascular events (MACEs). METHODS AND RESULTS: This was a multinational prospective cohort study, which included patients with heterozygous FH aged 18-65 years, without a prior history of CVD, and carrying a pathogenic or likely pathogenic variant in the LDLR gene. A total of 2131 patients (20 535person-years of follow-up) were included in the study, including 1234 subjects carrying a defective mutation in the LDLR and 897 subjects carrying a null mutation. During the follow-up, a first MACE occurred in 79 cases (6%) in the defective group and in 111 cases (12%) in the null group. The mean baseline LDL-C concentration was 17% higher in the null group than in the defective group (7.90 vs. 6.73 mmoL/L, P < 0.0001). In a Cox regression model corrected for traditional cardiovascular risk factors, the presence of a null mutation was associated with a hazard ratio of 2.09 (1.44-3.05), P = 0.0001. CONCLUSION: Carriers of a null mutation have an independent ∼2-fold increased risk of incident MACE compared with patients carrying a defective mutation. This study highlights the importance of genetic screening in FH in order to improve patient care.

Diagnosis of remnant hyperlipidaemia.

PURPOSE OF REVIEW: In recent years, there has been interest for the development of simplified diagnosis algorithms of dysbetalipoproteinemia (DBL) in order to avoid the complex testing associated with the Fredrickson criteria (reference method). The purpose of this review is to present recent advances in the field of DBL with a focus on screening and diagnosis. RECENT FINDINGS: Recently, two different multi-step algorithms for the diagnosis of DBL have been published and their performance has been compared to the Fredrickson criteria. Furthermore, a recent large study demonstrated that only a minority (38%) of DBL patients are carriers of the E2/E2 genotype and that these individuals presented a more severe phenotype. SUMMARY: The current literature supports the fact that the DBL phenotype is more heterogeneous and complex than previously thought. Indeed, DBL patients can present with either mild or more severe phenotypes that can be distinguished as multifactorial remnant cholesterol disease and genetic apolipoprotein B deficiency. Measurement of apolipoprotein B as well as APOE gene testing are both essential elements in the diagnosis of DBL.

Association between circulating PCSK9 and proteinuria in nephrotic syndrome: A cross-sectional study.

BACKGROUND: Nephrotic syndrome (NS) is associated with both hypercholesterolemia and hypertriglyceridemia, which could exacerbate disease progression and accelerate atherosclerosis. It has been reported that PCSK9, a proprotein convertase involved in hypercholesterolemia, was increased in patients with NS. OBJECTIVE: To investigate the association between PCSK9 concentrations and the magnitude of proteinuria. METHODS: A total of 168 patients from nephrology and lipid clinics of the Centre Hospitalier de l'Université de Montreal were included in this cross-sectional observational study. Proteinuria level was classified in three groups: nephrotic syndrome (n = 51), proteinuria (n = 66), and control (n = 51) according to proteinuria and albuminemia concentrations. Plasma PCSK9 concentration was measured by an in-house ELISA and the lipid profile was assayed using an automated biochemical analyzer (COBAS INTEGRA 400, Roche Diagnostic). RESULTS: Plasma PCSK9 concentration was highest in the NS group (170.9 ng/mL), intermediate in the proteinuria group (156.4 ng/mL) and lowest in the control group (136.0 ng/mL), P = 0.005. We observed an association between the protein/creatinine (P/C) ratio and plasma PCSK9 concentrations in the whole cohort (ß = 0.205, P = 0.006) after adjustment for age, sex, LDL-C, statin use, other lipid-lowering therapy use, diabetes, and eGFR. CONCLUSIONS: Patients with nephrotic syndrome have an increased risk of cardiovascular complications. PCSK9 is significantly elevated in NS and is associated with a detrimental lipid profile that could contribute to a worse prognosis of the disease. Future studies evaluating the efficacy of PCSK9 inhibitors in patients with NS would be justified.