Ethnic Diversity and Distinctive Features of Familial Versus Multifactorial Chylomicronemia Syndrome: Insights From the UK FCS National Registry.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS). METHODS: The study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project. RESULTS: FCS was relatively common in non-Europeans and those with parental consanguinity (P<0.001 for both). LPL variants were more common in European patients with FCS (European, 64%; non-European, 46%), while the genotype was more diverse in non-European patients with FCS. Patients with FCS had a higher incidence compared with patients with MCS of acute pancreatitis (84% versus 60%; P=0.001), recurrent pancreatitis (92% versus 63%; P<0.001), unexplained abdominal pain (84% versus 52%; P<0.001), earlier age of onset (median [interquartile range]) of symptoms (15.0 [5.5-26.5] versus 34.0 [25.2-41.7] years; P<0.001), and of acute pancreatitis (24.0 [10.7-31.0] versus 33.5 [26.0-42.5] years; P<0.001). Adverse cardiometabolic features and their co-occurrence was more common in individuals with MCS compared with those with FCS (P<0.001 for each). Atherosclerotic cardiovascular disease was more prevalent in individuals with MCS than those with FCS (P=0.04). However, this association became nonsignificant after adjusting for age, sex, and body mass index. The prevalence of pancreatic complications and cardiometabolic profile of variant-positive MCS was intermediate between FCS and variant-negative MCS. CONCLUSIONS: The frequency of gene variant distribution varies based on the ethnic origin of patients with FCS. Patients with FCS are at a higher risk of pancreatic complications while the prevalence of atherosclerotic cardiovascular disease is lower in FCS compared with MCS. Carriers of heterozygous pathogenic variants have an intermediate phenotype between FCS and variant-negative MCS.

Validation of the familial chylomicronaemia syndrome (FCS) score in an ethnically diverse cohort from UK FCS registry: Implications for diagnosis and differentiation from multifactorial chylomicronaemia syndrome (MCS).

BACKGROUND AND AIMS: Prognosis and management differ between familial chylomicronaemia syndrome (FCS), a rare autosomal recessive disorder, and multifactorial chylomicronaemia syndrome (MCS) or severe mixed hyperlipidaemia. A clinical scoring tool to differentiate these conditions has been devised but not been validated in other populations. The objective of this study was to validate this score in the UK population and identify any additional factors that might improve it. METHODS: A retrospective validation study was conducted using data from 151 patients comprising 75 FCS and 76 MCS patients. All participants had undergone genetic testing for genes implicated in FCS. Validation was performed by standard methods. Additional variables were identified from clinical data by logistic regression analysis. RESULTS: At the recommended FCS score threshold ≥10 points, the sensitivity and specificity of the score in the UK population were 96% and 75%, respectively. The receiver operating characteristic (ROC) curve analysis yielded an area under the curve (AUC) of 0.88 (95% CI 0.83-0.94, p < 0.001). This study identified non-European (predominantly South Asian) ethnicity, parental consanguinity, body mass index (BMI) < 25 kg/m2, and recurrent pancreatitis as additional positive predictors, while BMI >30 kg/m2 was found to be a negative predictor for FCS. However, inclusion of additional FCS predictors had no significant impact on performance of standard FCS score. CONCLUSIONS: Our study validates the FCS score in the UK population to distinguish FCS from MCS. While additional FCS predictors were identified, they did not improve further the score diagnostic performance.

Changes in PCSK 9 and apolipoprotein B100 in Niemann-Pick disease after enzyme replacement therapy with olipudase alfa.

BACKGROUND: Enzyme replacement therapy (ERT) with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is being developed to treat patients with ASM deficiency (ASMD), commonly known as Niemann-Pick disease (NPD) types A or B. This study assessed the effect of ERT on lipid parameters and inflammatory markers. METHODS: Serum and plasma samples from five adults with NPD type B (NPD-B) who received olipudase alfa ERT for 26 weeks were analysed. We also collected fasting blood samples from fifteen age- and sex-matched participants as reference and comparison group. We measured fasting lipid profile, apolipoproteins B48 and B100 (apoB48 and apoB100), apolipoprotein A1 (apoA1), proprotein convertase subtilisin/klexin type 9 (PCSK9) mass, oxidised low-density lipoprotein (oxLDL), small dense low-density lipoprotein cholesterol (sdLDL-C) and tumour necrosis factor α (TNF-α). RESULTS: Patients with NPD-B, compared with age and sex matched reference group, had higher triglycerides, PCSK9, apoB48, oxLDL and TNF-α and lower high density lipoprotein cholesterol (HDL-C) and apoA1. Treatment with ERT was associated with improved lipid parameters including total cholesterol, triglycerides, low density lipoprotein cholesterol (LDL-C), sdLDL-C, oxLDL and apoB100. Though there was an increase in apoA1, HDL-C was slightly reduced. TNF-α showed a reduction. ApoB100 decreased in parallel with a decrease in total serum PCSK9 mass after ERT. CONCLUSION: This study demonstrated that patients with NPD-B had a proatherogenic lipid profile and higher circulating TNF-α compared to reference group. There was an improvement in dyslipidaemia after olipudase alfa. It was possible that reductions in LDL-C and apoB100 were driven by reductions in TNF-α and PCSK9 following ERT.

Obesity: A critical risk factor in the COVID-19 pandemic.

Obesity is an emerging independent risk factor for susceptibility to and severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Previous viral pandemics have shown that obesity, particularly severe obesity (BMI > 40 kg/m2 ), is associated with increased risk of hospitalization, critical care admission and fatalities. In this narrative review, we examine emerging evidence of the influence of obesity on COVID-19, the challenges to clinical management from pulmonary, endocrine and immune dysfunctions in individuals with obesity and identify potential areas for further research. We recommend that people with severe obesity be deemed a vulnerable group for COVID-19; clinical trials of pharmacotherapeutics, immunotherapies and vaccination should prioritize inclusion of people with obesity.

Predicting intention to participate in self-management behaviors in patients with Familial Hypercholesterolemia: A cross-national study.

RATIONALE: Familial Hypercholesterolemia (FH) is a genetic condition that predisposes patients to substantially increased risk of early-onset atherosclerotic cardiovascular disease. FH risks can be minimized through regular participation in three self-management. BEHAVIORS: physical activity, healthy eating, and taking cholesterol lowering medication. OBJECTIVE: The present study tested the effectiveness of an integrated social cognition model in predicting intention to participate in the self-management behaviors in FH patients from seven countries. METHOD: Consecutive patients in FH clinics from Australia, Hong Kong, Brazil, Malaysia, Taiwan, China, and UK (total N = 726) completed measures of social cognitive beliefs about illness from the common sense model of self-regulation, beliefs about behaviors from the theory of planned behavior, and past behavior for the three self-management behaviors. RESULTS: Structural equation models indicated that beliefs about behaviors from the theory of planned behavior, namely, attitudes, subjective norms, and perceived behavioral control, were consistent predictors of intention across samples and behaviors. By comparison, effects of beliefs about illness from the common sense model were smaller and trivial in size. Beliefs partially mediated past behavior effects on intention, although indirect effects of past behavior on intention were larger for physical activity relative to taking medication and healthy eating. Model constructs did not fully account for past behavior effects on intentions. Variability in the strength of the beliefs about behaviors was observed across samples and behaviors. CONCLUSION: Current findings outline the importance of beliefs about behaviors as predictors of FH self-management behaviors. Variability in the relative contribution of the beliefs across samples and behaviors highlights the imperative of identifying sample- and behavior-specific correlates of FH self-management behaviors.

Comparative aspects of the care of familial hypercholesterolemia in the "Ten Countries Study".

BACKGROUND: There is a lack of information on the health care of familial hypercholesterolemia (FH). OBJECTIVE: The objective of this study was to compare the health care of FH in countries of the Asia-Pacific region and Southern Hemisphere. METHODS: A series of questionnaires were completed by key opinion leaders from selected specialist centers in 12 countries concerning aspects of the care of FH, including screening, diagnosis, risk assessment, treatment, teaching/training, and research; the United Kingdom (UK) was used as the international benchmark. RESULTS: The estimated percentage of patients diagnosed with the condition was low (overall <3%) in all countries, compared with ∼15% in the UK. Underdetection of FH was associated with government expenditure on health care (Ï° = 0.667, P < .05). Opportunistic and systematic screening methods, and the Dutch Lipid Clinic Network criteria were most commonly used to detect FH; genetic testing was infrequently used. Noninvasive imaging of coronary calcium and/or carotid plaques was underutilized in risk assessment. Patients with FH were generally not adequately treated, with <30% of patients achieving guideline recommended low-density lipoprotein cholesterol targets on conventional therapies. Treatment gaps included suboptimal availability and use of lipoprotein apheresis and proprotein convertase subtilsin-kexin type 9 inhibitors. A deficit of FH registries, training programs, and publications were identified in less economically developed countries. The demonstration of cost-effectiveness for cascade screening, genetic testing, and specialized treatments were significantly associated with the availability of subsidies from the health care system (Ï° = 0.571-0.800, P < .05). CONCLUSION: We identified important gaps across the continuum of care for FH, particularly in less economically developed countries. Wider implementation of primary and pediatric care, telehealth services, patient support groups, education/training programs, research activities, and health technology assessments are needed to improve the care of patients with FH in these countries.

Effects of medication, treatment, and behavioral beliefs on intentions to take medication in patients with familial hypercholesterolemia.

BACKGROUND AND AIMS: Although familial hypercholesterolemia (FH) can be effectively managed using cholesterol-lowering medication, patients often fall short of complete treatment adherence. Identifying the psychological factors associated with self-regulation of FH medication is important to inform interventions to maximize adherence. The aim of the present study was to test an integrated psychological model in predicting FH patients' intentions to take medication. METHODS: FH patients attending clinics in seven countries were invited to participate in a cross-sectional survey study. Consenting patients (N = 551) completed self-report measures of generalized beliefs about medication overuse and harms, beliefs in treatment effectiveness, specific beliefs about taking medication (attitudes, subjective norms, perceived behavioral control), and intentions to take medication. Participants also completed measures of demographic variables (age, gender, education level, income, cardiovascular disease status). Data were analysed using path analysis controlling for country and demographic variables. RESULTS: Attitudes (ß = .331, p<0.001), subjective norms (ß = .121, p=0.009), and beliefs about medication overuse (ß = -.160, p<0.001) were significant predictors of intentions to take medication. Treatment beliefs predicted intentions indirectly (ß = .088, p<0.001) through attitudes and subjective norms. There was also an indirect effect of beliefs about medication overuse on intentions (ß = -.045, p=0.056), but the effect was small compared with the direct effect. CONCLUSIONS: The findings indicate the importance among FH patients of specific beliefs about taking medication and generalized beliefs about medication overuse and treatment in predicting medication intentions. When managing patients, clinicians should emphasize the efficacy of taking cholesterol-lowering drugs and the importance of treatment outcomes, and allay concerns about medication overuse.

Health literacy in familial hypercholesterolemia: A cross-national study.

Background High rates of inadequate health literacy are associated with maladaptive health outcomes in chronic disease including increased mortality and morbidity rates, poor treatment adherence and poor health. Adequate health literacy may be an important factor in the effective treatment and management of familial hypercholesterolemia, and may also be implicated in genetic screening for familial hypercholesterolemia among index cases. The present study examined the prevalence and predictors of health literacy in familial hypercholesterolemia patients attending clinics in seven countries. Design Cross-sectional survey. Methods Consecutive FH patients attending clinics in Australia, Brazil, China, Hong Kong, Malaysia, Taiwan and the UK completed measures of demographic variables (age, gender, household income and highest education level) and a brief three-item health literacy scale. Results Rates of inadequate health literacy were lowest in the UK (7.0%), Australia (10.0%), Hong Kong (15.7%) and Taiwan (18.0%) samples, with higher rates in the Brazil (22.0%), Malaysia (25.0%) and China (37.0%) samples. Income was an independent predictor of health literacy levels, accounting for effects of age. Health literacy was also independently related to China national group membership. Conclusions Findings indicate non-trivial levels of inadequate health literacy in samples of familial hypercholesterolemia patients. Consistent with previous research in chronic illness, inadequate health literacy is related to income as an index of health disparities. Chinese familial hypercholesterolemia patients are more likely to have high rates of inadequate health literacy independent of income. Current findings highlight the imperative of education interventions targeting familial hypercholesterolemia patients with inadequate health literacy.

Hypercholesterolaemia - practical information for non-specialists.

Hypercholesterolaemia is amongst the most common conditions encountered in the medical profession. It remains one of the key modifiable cardiovascular risk factors and there have been recent advances in the risk stratification methods and treatment options available. In this review, we provide a background into hypercholesterolaemia for non-specialists and consider the merits of the different risk assessment tools available. We also provide detailed considerations as to: i) when to start treatment, ii) what targets to aim for and iii) the role of low density lipoprotein cholesterol.

A comparison of the effects of low- and high-dose atorvastatin on lipoprotein metabolism and inflammatory cytokines in type 2 diabetes: Results from the Protection Against Nephropathy in Diabetes with Atorvastatin (PANDA) randomized trial.

BACKGROUND: Statin therapy is recommended in type 2 diabetes (T2DM) although views on treatment intensity and therapeutic targets remain divided. OBJECTIVES: Our objectives were to compare the effects of high-intensity and moderate-intensity atorvastatin treatment on lipoprotein metabolism and inflammatory markers and how frequently treatment goals are met in high-risk T2DM patients. METHODS: Patients with T2DM and albuminuria (urinary albumin:creatinine ratio >5 mg/mmol, total cholesterol <7 mmol/L, proteinuria <2 g/d, creatinine <200 µmol/L) were randomized to receive atorvastatin 10 mg (n = 59) or 80 mg (n = 60) daily. Baseline and 1-year follow-up data are reported. RESULTS: Patients were at high cardiovascular disease risk (observed combined mortality and nonfatal cardiovascular disease annual event rate 4.8%). The non-high-density lipoprotein cholesterol (HDL-C) goal of <2.6 mmol/L was achieved in 72% of participants receiving high-dose atorvastatin, but only in 40% on low-dose atorvastatin (P < .005). The proportion achieving apolipoprotein B (apoB) <0.8 g/L on high-dose and low-dose atorvastatin was 82% and 70%, respectively (NS). Total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, non-HDL-C, oxidized LDL, apoB, glyc-apoB, apolipoprotein E, and lipoprotein-associated phospholipase A2 decreased significantly, more so in participants on high-dose atorvastatin. Adiponectin increased and serum amyloid A decreased without dose dependency. Neither dose produced significant changes in HDL-C, cholesterol efflux, high-sensitivity C-reactive protein, glycated hemoglobin, serum paraoxonase-1, lecithin:cholesterol acyltransferase, or cholesteryl ester transfer protein. CONCLUSIONS: High-dose atorvastatin is more effective in achieving non-HDL-C therapeutic goals and in modifying LDL-related parameters. Recommended apoB treatment targets may require revision. Despite the increase in adiponectin and the decrease in serum amyloid A, HDL showed no change in functionality.