Generation and validation of a classification model to diagnose familial hypercholesterolaemia in adults.

BACKGROUND AND AIMS: The early diagnosis of familial hypercholesterolaemia is associated with a significant reduction in cardiovascular disease (CVD) risk. While the recent use of statistical and machine learning algorithms has shown promising results in comparison with traditional clinical criteria, when applied to screening of potential FH cases in large cohorts, most studies in this field are developed using a single cohort of patients, which may hamper the application of such algorithms to other populations. In the current study, a logistic regression (LR) based algorithm was developed combining observations from three different national FH cohorts, from Portugal, Brazil and Sweden. Independent samples from these cohorts were then used to test the model, as well as an external dataset from Italy. METHODS: The area under the receiver operating characteristics (AUROC) and precision-recall (AUPRC) curves was used to assess the discriminatory ability among the different samples. Comparisons between the LR model and Dutch Lipid Clinic Network (DLCN) clinical criteria were performed by means of McNemar tests, and by the calculation of several operating characteristics. RESULTS: AUROC and AUPRC values were generally higher for all testing sets when compared to the training set. Compared with DLCN criteria, a significantly higher number of correctly classified observations were identified for the Brazilian (p < 0.01), Swedish (p < 0.01), and Italian testing sets (p < 0.01). Higher accuracy (Acc), G mean and F1 score values were also observed for all testing sets. CONCLUSIONS: Compared to DLCN criteria, the LR model revealed improved ability to correctly classify observations, and was able to retain a similar number of FH cases, with less false positive retention. Generalization of the LR model was very good across all testing samples, suggesting it can be an effective screening tool if applied to different populations.

Clinical Approach in the Management of Paediatric Patients with Familial Hypercholesterolemia: A National Survey Conducted by the LIPIGEN Paediatric Group.

Detection and treatment of patients with familial hypercholesterolemia (FH) starting from childhood is fundamental to reduce morbidity and mortality. The activity of National realities such as the LIPIGEN (LIpid transPort disorders Italian GEnetic Network) Paediatric Group, founded in 2018, is a milestone in this context. The aim of this exploratory survey, conducted in October 2021 among Italian lipid clinics included in the LIPIGEN Paediatric Group, was to investigate the current clinical approach in the management and treatment of paediatric patients with suspected FH. A digital questionnaire composed of 20 questions investigating nutritional treatment and nutraceutical and pharmacological therapy for children and adolescents with FH was proposed to the principal investigators of 30 LIPIGEN centres. Twenty-four centres responded to the section referring to children aged < 10 years and 30 to that referring to adolescents. Overall, 66.7% of children and 73.3% of adolescents were given lipid-lowering nutritional treatment as the first intervention level for at least 3-4 months (29.2% and 23.3%) or 6-12 months (58.3% and 53.3%). Nutraceuticals were considered in 41.7% (regarding children) and 50.0% (regarding adolescents) of the centres as a supplementary approach to diet. Lipid-lowering drug therapy initiation was mainly recommended (91.7% and 80.0%). In 83.3% of children and 96.7% of adolescents, statins were the most frequently prescribed drug. We highlighted several differences in the treatment of paediatric patients with suspected FH among Italian centres; however, the overall approach is in line with the European Atherosclerosis Society (EAS) recommendations for FH children and adolescents. We consider this survey as a starting point to reinforce collaboration between LIPIGEN centres and to elaborate in the near future a consensus document on the management of paediatric patients with suspected FH so as to improve and uniform detection, management, and treatment of these patients in our country.

A subgroup analysis of the ODYSSEY APPRISE study: Safety and efficacy of alirocumab in the Italian cohort.

BACKGROUND AND AIMS: ODYSSEY APPRISE trial evaluated efficacy and safety of alirocumab in 994 patients with hypercholesterolemia and high CV risk in a real-life setting. The aim of the present report is to detail on the Italian cohort enrolled and treated in the trial. METHODS AND RESULTS: The methodology of the of the multinational, single-arm, Phase 3b open-label ODYSSEY APPRISE (Clinicaltrials.gov: NCT02476006) has been previously reported. 255 Italian patients were enrolled and treated according to the trial protocol. Overall mean exposure to alirocumab was 83.3 ± 27.7 weeks. At week 12, LDL-C decreased by 51.3 ± 23.1% and this reduction was overall maintained for the duration of the study. A similar reduction was observed in patients with and without heterozygous familial hypercholesterolemia (HeFH 50.7% ± 23.9 vs. non-FH, 53.6% ± 19.6). LDL-C was reduced below 1.8 mmol/L and/or by ≥ 50% reduction from baseline in 62% of patients overall (61% in HeFH and 67% in non-FH). Alirocumab was similarly well tolerated in the Italian cohort as in the entire study population and the more common treatment emergent adverse events (TEAEs) were influenza, myalgia and nasopharyngitis. The incidence LDL-C levels <25 mg/dl and <15 mg/dl, was 8.2% and 2.9% respectively. CONCLUSION: The efficacy and safety of alirocumab in a real-life setting, in the Italian subgroup of patients are consistent with findings in the entire study population and confirm that alirocumab is a beneficial approach to further reduce LDL-C levels in patients at high CV risk on maximally tolerated conventional lipid lowering treatment. GOV IDENTIFIER: NCT02476006.

Effects of PCSK9 inhibitors on HDL cholesterol efflux and serum cholesterol loading capacity in familial hypercholesterolemia subjects: a multi-lipid-center real-world evaluation.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond regulating LDL cholesterol (LDL-c) plasma levels, exerts several pleiotropic effects by modulating lipid metabolism in extrahepatic cells such as macrophages. Macrophage cholesterol homeostasis depends on serum lipoprotein functions, including the HDL capacity to promote cell cholesterol efflux (CEC) and the serum capacity to promote cell cholesterol loading (CLC). The aim of this observational study was to investigate the effect of PCSK9 inhibitors (PCSK9-i) treatment on HDL-CEC and serum CLC in patients with familial hypercholesterolemia (FH). 31 genetically confirmed FH patients were recruited. Blood was collected and serum isolated at baseline and after 6 months of PCSK9-i treatment. HDL-CEC was evaluated through the main pathways with a radioisotopic cell-based assay. Serum CLC was assessed fluorimetrically in human THP-1 monocyte-derived macrophages. After treatment with PCSK9-i, total cholesterol and LDL-c significantly decreased (-41.6%, p < 0.0001 and -56.7%, p < 0.0001, respectively). Total HDL-CEC was not different between patients before and after treatment. Conversely, despite no changes in HDL-c levels between the groups, ABCG1 HDL-CEC significantly increased after treatment (+22.2%, p < 0.0001) as well as HDL-CEC by aqueous diffusion (+7.8%, p = 0.0008). Only a trend towards reduction of ABCA1 HDL-CEC was observed after treatment. PCSK9-i significantly decreased serum CLC (-6.6%, p = 0.0272). This effect was only partly related to the reduction of LDL-c levels. In conclusion, PCSK9-i treatment significantly increased HDL-CEC through ABCG1 and aqueous diffusion pathways and reduced the serum CLC in FH patients. The favorable effect of PCSK9-i on functional lipid profile could contribute to the cardiovascular benefit of these drugs in FH patients.

Interactions of Oxysterols with Atherosclerosis Biomarkers in Subjects with Moderate Hypercholesterolemia and Effects of a Nutraceutical Combination (Bifidobacterium longum BB536, Red Yeast Rice Extract) (Randomized, Double-Blind, Placebo-Controlled Study).

BACKGROUND: Oxysterol relationship with cardiovascular (CV) risk factors is poorly explored, especially in moderately hypercholesterolaemic subjects. Moreover, the impact of nutraceuticals controlling hypercholesterolaemia on plasma levels of 24-, 25- and 27-hydroxycholesterol (24-OHC, 25-OHC, 27-OHC) is unknown. METHODS: Subjects (n = 33; 18-70 years) with moderate hypercholesterolaemia (low-density lipoprotein cholesterol (LDL-C:): 130-200 mg/dL), in primary CV prevention as well as low CV risk were studied cross-sectionally. Moreover, they were evaluated after treatment with a nutraceutical combination (Bifidobacterium longum BB536, red yeast rice extract (10 mg/dose monacolin K)), following a double-blind, randomized, placebo-controlled design. We evaluated 24-OHC, 25-OHC and 27-OHC levels by gas chromatography/mass spectrometry analysis. RESULTS: 24-OHC and 25-OHC were significantly correlated, 24-OHC was correlated with apoB. 27-OHC and 27-OHC/total cholesterol (TC) were higher in men (median 209 ng/mL and 77 ng/mg, respectively) vs. women (median 168 ng/mL and 56 ng/mg, respectively); 27-OHC/TC was significantly correlated with abdominal circumference, visceral fat and, negatively, with high-density lipoprotein cholesterol (HDL-C). Triglycerides were significantly correlated with 24-OHC, 25-OHC and 27-OHC and with 24-OHC/TC and 25-OHC/TC. After intervention, 27-OHC levels were significantly reduced by 10.4% in the nutraceutical group Levels of 24-OHC, 24-OHC/TC, 25-OHC, 25-OHC/TC and 27-OHC/TC were unchanged. CONCLUSIONS: In this study, conducted in moderate hypercholesterolemic subjects, we observed novel relationships between 24-OHC, 25-OHC and 27-OHC and CV risk biomarkers. In addition, no adverse changes of OHC levels upon nutraceutical treatment were found.

Correction to: Nutraceutical approach for the management of cardiovascular risk - a combination containing the probiotic Bifidobacterium longum BB536 and red yeast rice extract: results from a randomized, double-blind, placebo-controlled study.

Following publication of the original article [1], the authors reported an error in the affiliation of the third author, Sara Gandini. The correct affiliation should read: Division of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, Milan, Italy.

Nutraceutical approach for the management of cardiovascular risk - a combination containing the probiotic Bifidobacterium longum BB536 and red yeast rice extract: results from a randomized, double-blind, placebo-controlled study.

BACKGROUND: Probiotics incorporated into dairy products have been shown to reduce total (TC) and LDL cholesterolemia (LDL-C) in subjects with moderate hypercholesterolemia. More specifically, probiotics with high biliary salt hydrolase activity, e.g. Bifidobacterium longum BB536, may decrease TC and LDL-C by lowering intestinal cholesterol reabsorption and, combined with other nutraceuticals, may be useful to manage hypercholesterolemia in subjects with low cardiovascular (CV) risk. This study was conducted to evaluate the efficacy and safety of a nutraceutical combination containing Bifidobacterium longum BB536, red yeast rice (RYR) extract (10 mg/day monacolin K), niacin, coenzyme Q10 (Lactoflorene Colesterolo®). The end-points were changes of lipid CV risk markers (LDL-C, TC, non-HDL-cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (ApoB), HDL-C, apolipoprotein AI (ApoAI), lipoprotein(a) (Lp(a), proprotein convertase subtilisin/kexin type 9 (PCSK9)), and of markers of cholesterol synthesis/absorption. METHODS: A 12-week randomized, parallel, double-blind, placebo-controlled study. Thirty-three subjects (18-70 years) in primary CV prevention and low CV risk (SCORE: 0-1% in 24 and 2-4% in 9 subjects; LDL-C: 130-200 mg/dL) were randomly allocated to either nutraceutical (N = 16) or placebo (N = 17). RESULTS: Twelve-week treatment with the nutraceutical combination, compared to placebo, significantly reduced TC (- 16.7%), LDL-C (- 25.7%), non-HDL-C (- 24%) (all p < 0.0001), apoB (- 17%, p = 0.003). TG, HDL-C, apoAI, Lp(a), PCSK9 were unchanged. Lathosterol:TC ratio was significantly reduced by the nutraceutical combination, while campesterol:TC ratio and sitosterol:TC ratio did not change, suggesting reduction of synthesis without increased absorption of cholesterol. No adverse effects and a 97% compliance were observed. CONCLUSIONS: A 12-week treatment with a nutraceutical combination containing the probiotic Bifidobacterium longum BB536 and RYR extract significantly improved the atherogenic lipid profile and was well tolerated by low CV risk subjects. TRIAL REGISTRATION: NCT02689934 .

Influence of body variables in the development of metabolic syndrome-A long term follow-up study.

OBJECTIVES: The body variable associated with the diagnosis of Metabolic Syndrome (MetS) is an elevated waist circumference (WC), although a number of other variables have been suggested. Among these, an elevated waist-to-height ratio (WHtR), ie a value higher than 0.5, that may identify abnormality, independently from height. An elevated WHtR provided the best correlation with MetS in a prior study in a large Italian population. In order to assess the validity of this conclusion, a long-term follow-up study re-examined this population, also in order to detect possible associations with cardiovascular (CV) risk. METHODS AND RESULTS: 1,071 subjects with a complete follow-up of over 6 years were evaluated with a comparative assessment of the three anthropometric variables, namely WHtR, WC and body mass index (BMI). WHtR≥ 0.5 had the highest sensitivity for the identification of MetS, both in males and females (94.1% and 86.7% respectively). WHtR was of reduced specificity, occurring, yet less frequently (17.7% in males and 30% in females), in patients without MetS. By contrast, enlarged WC occurred with a lower frequency in male patients who developed MetS (30.2%) whereas in females, frequency was higher than in males (69.3%). Finally, a BMI≥ 25 kg/m2 had intermediate sensitivity and specificity regardless of gender. WC showed the highest odds ratio (2.62, 95%CI: 1.18-5.78) for the prediction of CV occurrence. CONCLUSION: The present study confirms WHtR as an excellent screening tool in identifying MetS carriers, but, different from reports in other countries, it shows a lower specificity in our population.

Systematic Lab Knowledge Integration for Management of Lipid Excess in High-Risk Patients: Rationale and Design of the SKIM LEAN Project.

SKIM LEAN aims at exploiting Electronic Health Records (EHRs) to integrate knowledge derived from routine laboratory tests with background analysis of clinical databases, for the identification and early referral to specialist care, where appropriate, of patients with hypercholesterolemia, who may be inadequately controlled according to their cardiovascular (CV) risk level. SKIM LEAN addresses gaps in care that may occur through the lack of coordination between primary and specialist care, incomplete adherence to clinical guidelines, or poor patient's compliance to the physician's prescriptions because of comorbidities or drug side effects. Key project objectives include: (1) improved health professionals' competence and patient empowerment through a two-tiered educational website for general practitioners (GPs) and patients, and (2) implementation of a hospital-community shared care pathway to increase the proportion of patients at high/very-high CV risk (Familial Hypercholesterolemia, previous CV events) who achieve target LDL cholesterol (LDL-C) levels. Thanks to a close collaboration between clinical and information technology partners, SKIM LEAN will fully exploit the value of big data deriving from EHRs, and filter such knowledge using clinically-derived algorithms to risk-stratify patients. Alerts for GPs will be generated with interpreted test results. GPs will be able to refer patients with uncontrolled LDL-C within the shared pathway to the lipid or secondary prevention outpatient clinics of NIG hospital. Metrics to verify the project achievements include web-site visits, the number of alerts generated, numbers of patients referred by GPs, the proportion of secondary prevention patients who achieve LDL-C <100 mg/dl or a >50% decrease from baseline.

Effect of a food supplement containing berberine, monacolin K, hydroxytyrosol and coenzyme Q10 on lipid levels: a randomized, double-blind, placebo controlled study.

PURPOSE: To evaluate the ability of the new food supplement, Body Lipid (BL), containing red yeast rice, berberine, coenzyme Q10 and hydroxytyrosol, to lower the LDL-C in patients with mild-to-moderate hypercholesterolemia and to assess the overall safety profile of the product. METHODS: In this multicenter, randomized, double-blind, placebo and active comparator (the marketed Armolipid Plus® [AM]) controlled study, 158 hypercholesterolemic patients were randomized following a 4-week dietary run-in period. After 4 weeks of treatment with a daily oral dose of the new food supplement BL, AM or placebo, plus diet, the main outcome was the decrease of LDL-C, total cholesterol (TC), and triglyceride levels. FINDINGS: The absolute changes of LDL-C and TC levels from baseline, at week 4 were: -39.1 mg/dL ±17.76 and -45.9 mg/dL ±21.54, respectively in the BL group; 5.7 mg/dL ±14.98 and 2.4 mg/dL ±18.43, respectively in the placebo group. Results were statistically significant. In terms of mean percentage, BL was shown to be more effective in lowering LDL-C levels as compared to placebo and the active comparator (AM), with a reduction of -26.3%, +4.2%, -18.3%, respectively. Five adverse events (AEs) were reported by five patients after the initiation of the study treatment: two in the BL group (influence and insomnia), two in the AM group (ear pain and rash), and one in the placebo group (back pain). All AEs were mild in intensity, except for back pain (severe). The case of insomnia in the BL group and the case of rash in the AM group were judged as treatment related. The safety review of the laboratory (blood and urine) analyses, vital signs and physical findings did not show any clinical effect of the study products on any of the parameters. IMPLICATIONS: BL showed a good efficacy and safety profile and, for this reason, it can be considered an alternative to pharmacological treatment, for patients with mild-to-moderate hypercholesterolemia.

Indicators of Cardiovascular Risk in Metabolic Syndrome: Long Term Follow-up in Italian Patients.

BACKGROUND: Cardiovascular risk (CV) factors associated with the metabolic syndrome (MetS) may vary in different populations. In some, hypertension may be the major determinant, in others are low high-density lipoprotein cholesterol (HDL-C), high triglycerides, or another component. SUBJECTS AND METHODS: Subjects included in this analysis were identified in 2006, among those attending the Lipid Clinic of the Niguarda Hospital, and followed up through to 2013. Patient characteristics (including the occurrence of CV events) were obtained from electronic medical records. MetS was diagnosed according to the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) guidelines. The carotid intima media thickness (cIMT) was also followed in these patients over the years. RESULTS: After 7 years a total of 858 subjects had a complete follow-up; 271 of those had MetS. Patients developing a CV event showed elevated baseline cIMT (e.g. cIMTmax ≥ 2.4 mm in males and ≥ 2.2 mm in females); moreover the cIMT in MetS patients was higher at baseline and the rise over 7 years was larger compared with patients without MetS. By examining each body variable for MetS we found that a waist to height ratio (WHtR) ≥ 0.5 was present in nearly all subjects with a CV event. CONCLUSION: The follow-up data of a series of Italian patients with and without MetS, clearly indicates that the former have a raised cIMT and their arterial IMT progression is greater and the presence of a larger WHtR is apparently linked to a higher incidence of CV events.

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders.

OBJECTIVE: To validate new mitochondrial myopathy serum biomarkers for diagnostic use. METHODS: We analyzed serum FGF21 (S-FGF21) and GDF15 from patients with (1) mitochondrial diseases and (2) nonmitochondrial disorders partially overlapping with mitochondrial disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in mitochondrial disease and (4) analyzed S-Fgf21 and skeletal muscle Fgf21 expression in 6 mouse models with different muscle-manifesting mitochondrial dysfunctions. RESULTS: We report that S-FGF21 consistently increases in primary mitochondrial myopathy, especially in patients with mitochondrial translation defects or mitochondrial DNA (mtDNA) deletions (675 and 347 pg/mL, respectively; controls: 66 pg/mL, p < 0.0001 for both). This is corroborated in mice (mtDNA deletions 1,163 vs 379 pg/mL, p < 0.0001). However, patients and mice with structural respiratory chain subunit or assembly factor defects showed low induction (human 335 pg/mL, p < 0.05; mice 335 pg/mL, not significant). Overall specificities of FGF21 and GDF15 to find patients with mitochondrial myopathy were 89.3% vs 86.4%, and sensitivities 67.3% and 76.0%, respectively. However, GDF15 was increased also in a wide range of nonmitochondrial conditions. CONCLUSIONS: S-FGF21 is a specific biomarker for muscle-manifesting defects of mitochondrial translation, including mitochondrial transfer-RNA mutations and primary and secondary mtDNA deletions, the most common causes of mitochondrial disease. However, normal S-FGF21 does not exclude structural respiratory chain complex or assembly factor defects, important to acknowledge in diagnostics. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that elevated S-FGF21 accurately distinguishes patients with mitochondrial myopathies from patients with other conditions, and FGF21 and GDF15 mitochondrial myopathy from other myopathies.

Gender-related lipid and/or lipoprotein responses to statins in subjects in primary and secondary prevention.

BACKGROUND: Cardiovascular risk in men rises around the fourth decade of life, whereas women appear to be protected by sex hormones until menopause. This, in turn, tends to negatively affect the lipid profile. Since the 1980s, the incidence of cardiovascular diseases has been reported to progressively decline in men, but it has persisted almost unchanged in women. Major clinical trials on statins have been mostly conducted in men and have fostered the introduction of these agents into clinical practice worldwide. However, only few reports have examined a possible differential activity of statins in the 2 genders, providing in some cases opposite findings. OBJECTIVE: To evaluate gender-related differences in statin responses. METHODS: Variations of lipid profile after 1-year of treatment with different statins in 337 dyslipidemic patients (171 men and 166 women). RESULTS: In this series of patients, a significantly attenuated reduction of total cholesterol and low-density lipoprotein cholesterol in women vs men on drug treatment was noted after adjustment for dose and statin power (low-density lipoprotein cholesterol: -28.5 ± 11.8% in men vs -22.7 ± 11.8% in women; P < .001). CONCLUSIONS: The present study indicates that statin treatment has a reduced effectiveness in improving the plasma lipid profile in dyslipidemic women vs men. Whether such gender-related differences may have an impact on clinical outcomes remains to be elucidated.

Nutraceutical approach to moderate cardiometabolic risk: results of a randomized, double-blind and crossover study with Armolipid Plus.

BACKGROUND: Primary cardiovascular prevention may be achieved by lifestyle/nutrition improvements and specific drugs, although a relevant role is now emerging for specific functional foods and nutraceuticals. OBJECTIVES: The aim of this study was to evaluate the usefulness of a nutraceutical multitarget approach in subjects with moderate cardiovascular risk and to compare it with pravastatin treatment. SUBJECTS: Thirty patients with moderate dyslipidemia and metabolic syndrome (according to the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults) were included in an 8-week randomized, double-blind crossover study and took either placebo or a nutraceutical combination that contained red yeast rice extract, berberine, policosanol, astaxanthin, coenzyme Q10, and folic acid (Armolipid Plus). Subsequently, they were subjected to another 8-week treatment with pravastatin 10 mg/d. This dosage was selected on the basis of its expected -20% efficacy in reducing low-density lipoprotein-cholesterol. RESULTS: Treatment with Armolipid Plus led to a significant reduction of total cholesterol (-12.8%) and low-density lipoprotein-cholesterol (-21.1%), similar to pravastatin (-16% and -22.6%, respectively), and an increase of high-density lipoprotein-cholesterol (4.8%). Armolipid Plus improved the leptin-to-adiponectin ratio, whereas adiponectin levels were unchanged. CONCLUSIONS: These results indicate that this nutraceutical approach shows a lipid-lowering activity comparable to pravastatin treatment. Hence, it may be a safe and useful option, especially in conditions of moderate cardiovascular risk, in which a pharmacologic intervention may not be appropriate.

Novel therapeutic strategies for the homozygous familial hypercholesterolemia.

HoFH is an autosomal co-dominant disease with a prevalence of one in 1,000,000. Mutations of LDL-R gene are responsible for this disease. HoFH needs to be distinguished from autosomal recessive hypercholesterolemia protein (ARH) that causes a similar clinical phenotype. HoFH induces aggressive cardiovascular disease that can develop from birth. These patients possess high LDL-C levels, cutaneous and tendon xanthomas, and accelerated atherosclerosis shown in the first 2 decades of life. Current treatment modalities include life-style modifications, lipid-lowering therapy and LDL-apheresis. However, the treatment goal cannot be achieved only by statin therapy. New therapeutic strategies to lower LDL-C have been developed over recent years. These include monoclonal antibodies binding to PCSK9, inhibition of ApoB production and MTP-inhibitors. This review is focused on new treatments for HoFH and their patents. It is known to be an important contribution in this rare disease, which is difficult to manage.

Severe high-density lipoprotein deficiency associated with autoantibodies against lecithin:cholesterol acyltransferase in non-Hodgkin lymphoma.

An antibody against the lecithin:cholesterol acyltransferase (LCAT) enzyme, which negates cholesterol esterification in plasma, causing severe high-density lipoprotein deficiency (HD), was identified in a woman with a large-cell non-Hodgkin lymphoma. Successful treatment of the lymphoma resulted in clearance of the antibody and complete correction of the defective cholesterol esterification and HD. To our knowledge, an acquired LCAT deficiency leading to severe HD has not been reported previously in association with a malignant disease, and this patient represents the first such documented case.

Clinical response to statins: mechanism(s) of variable activity and adverse effects.

Statins represent a major advance in the treatment of hypercholesterolemia, a significant risk factor for atherosclerosis. There is, however, notable interindividual variation in the cholesterolemic response to statins, and the origin of this variability is poorly understood; pharmacogenetics has attempted to determine the role of genetic factors. Myopathy, further, has been reported in a considerable percentage of patients, but the mechanisms underlying muscle injury have yet to be fully characterized. Most statins are the substrates of several cytochrome P450s (CYP). CYP polymorphisms may be responsible for variations in hypolipidemic activity; inhibitors of CYPs, e.g. of CYP3A4, can significantly raise plasma concentrations of several statins, but consequences in terms of clinical efficacy are not uniform. Pravastatin and rosuvastatin are not susceptible to CYP inhibition but are substrates of the organic anion-transporting polypeptide (OATP) 1B1, encoded by the SLCO1B1 gene. Essentially all statins are, in fact, substrates of membrane transporters: SLCO1B1 polymorphisms can decrease the liver uptake, as well as the therapeutic potential of these agents, and may be linked to their muscular side-effects. A better understanding of the mechanisms of statin handling will help to minimize adverse effects and interactions, as well as to improve their lipid-lowering efficiency.

Hypocholesterolaemic effects of lupin protein and pea protein/fibre combinations in moderately hypercholesterolaemic individuals.

The present study was aimed to evaluate the effect of plant proteins (lupin protein or pea protein) and their combinations with soluble fibres (oat fibre or apple pectin) on plasma total and LDL-cholesterol levels. A randomised, double-blind, parallel group design was followed: after a 4-week run-in period, participants were randomised into seven treatment groups, each consisting of twenty-five participants. Each group consumed two bars containing specific protein/fibre combinations: the reference group consumed casein+cellulose; the second and third groups consumed bars containing lupin or pea proteins+cellulose; the fourth and fifth groups consumed bars containing casein and oat fibre or apple pectin; the sixth group and seventh group received bars containing combinations of pea protein and oat fibre or apple pectin, respectively. Bars containing lupin protein+cellulose ( - 116 mg/l, - 4·2%), casein+apple pectin ( - 152 mg/l, - 5·3%), pea protein+oat fibre ( - 135 mg/l, - 4·7%) or pea protein+apple pectin ( - 168 mg/l, - 6·4%) resulted in significant reductions of total cholesterol levels (P<0·05), whereas no cholesterol changes were observed in the subjects consuming the bars containing casein+cellulose, casein+oat fibre or pea protein+cellulose. The present study shows the hypocholesterolaemic activity and potential clinical benefits of consuming lupin protein or combinations of pea protein and a soluble fibre, such as oat fibre or apple pectin.