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Familial hypercholesterolemia (FH) is the most common monogenic disorder causing premature atherosclerotic cardiovascular disease. It affects 1 in 250 individuals worldwide, and of the approximately 145,000 Canadians estimated to have FH, most are undiagnosed. Herein, we provide an update of the 2014 Canadian Cardiovascular Society position statement on FH addressing the need for case identification, prompt recognition, and treatment with statins and ezetimibe, and cascade family screening. We provide a new Canadian definition for FH and tools for clinicians to make a diagnosis. The risk of atherosclerotic cardiovascular disease in patients with "definite" FH is 10- to 20-fold that of a normolipidemic individual and initiating treatment in youth or young adulthood can normalize life expectancy. Target levels for low-density lipoprotein cholesterol are proposed and are aligned with the Canadian Cardiovascular Society guidelines on dyslipidemia. Recommendation for the use of inhibitors of proprotein convertase kexin/subtilisin type 9 are made in patients who cannot achieve therapeutic low-density lipoprotein cholesterol targets on maximally tolerated statins and ezetimibe. The writing committee used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology in the preparation of the present document, which offers guidance for practical evaluation and management of patients with FH. This position statement also aims to raise awareness of FH nationally, and to mobilize patient support, promote knowledge translation, and availability of treatment and health care resources for this under-recognized, but important medical condition.

KEY POINTS A 72-year-old woman from southwestern Ontario was admitted to hospital with a 2-month history of progressive generalized weakness, fatigue, nausea, anorexia and 7-kg weight loss. Although previously functionally independent, she now required a walker for ambulation. She had also noted

Background: The numbers of women attending Diabetes and Pregnancy Clinics (DPC) are increasing. Some of the increase may reflect obesity effects on GDM prevalence, but numbers and characteristics of women with type 2 (T2DM) diabetes are unknown. The DPC in London Ontario sees all pregnant women with diabetes within the catchment area with stable clinic structures and procedures. Longitudinal characteristics of women with T2DM were documented for demographic insights. Methods: DPC pregnancy charts were assessed for 2000-2002, 2010-2012 and 2014-2016. Data were abstracted for: age; weight, A1C and medication use. Continuous results were analyzed by one-way analysis of variance (ANOVA); non-parametric results by Chi-square testing; p≤ 0.05 signifying significance. Conclusions: Numbers of pregnant women with T2DM increased significantly by 40% with time. Mean weights were lower in the second and third time interval. A1C values were lower by final visit in all time periods. Oral agent use increased in the final time period coincident with increased clinical comfort using metformin. Disclosure L. Chow: None. K. Anukam: None. P. Khanna: None. E. Brydges: None. S.L. Liu: Consultant; Self; Novo Nordisk Inc., Sanofi. Research Support; Self; Physicians' Services Inc. Foundation. J. Mahon: None. T.R. Joy: Speaker's Bureau; Self; Amgen Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Amgen Inc., AstraZeneca, Novo Nordisk Inc. R.M. McManus: None.

Background: Numbers of women attending Diabetes and Pregnancy Clinics (DPC) are increasing. Potential reasons include: obesity; fertility intervention access; diagnostic changes for gestational diabetes (GDM). The DPC in London Ontario sees all pregnant women with diabetes within the catchment area with stable clinic structure and procedures. Longitudinal characteristics of GDM women were documented for demographic insights. Methods: DPC pregnancy charts were assessed for 2000-2002, 2010-2012 and 2014-2016. Data were abstracted for: age; weight, infertility interventions; GDM diagnostic method. Continuous results were analyzed by one-way analysis of variance (ANOVA), non-parametric results by Chi-square testing; p≤ 0.05 signifying significance. Conclusions: Over the study interval, women with a GDM diagnosis increased 240%. The change may be related to obesity; changes to GDM diagnostic criteria and week of testing; but not late pregnancy weight gain or use of fertility interventions. Disclosure P. Khanna: None. K. Anukam: None. L. Chow: None. E. Brydges: None. S.L. Liu: Consultant; Self; Novo Nordisk Inc., Sanofi. Research Support; Self; Physicians' Services Inc. Foundation. J. Mahon: None. T.R. Joy: Speaker's Bureau; Self; Amgen Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Amgen Inc., AstraZeneca, Novo Nordisk Inc. R.M. McManus: None.

Background: The numbers of women attending Diabetes and Pregnancy Clinics (DPC) are increasing. Some of the increase may reflect obesity effects on GDM prevalence, but changes in numbers and characteristics of women with type 1 diabetes (T1DM) are unknown. The DPC in London Ontario sees all pregnant women with diabetes within the catchment area with stable clinic structures and procedures. Longitudinal characteristics of women with T1DM were documented for demographic insights. Methods: DPC pregnancy charts were assessed for 2000-2002, 2010-2012 and 2014-2016. Data were abstracted for: age; weight, A1C and medication use. Continuous results were analyzed by one-way analysis of variance (ANOVA); non-parametric results by Chi-square testing; p≤ 0.05 signifying significance. Conclusions: Clinic numbers of pregnant women with T1DM increased non-significantly over the study timeline while pump usage rose concurrent with access to government funding. A1C values fell 0.5% from first to last visit in all time periods. A1C values at first visit rose over the time periods suggesting women with less optimal glucose control were conceiving pregnancies. Disclosure P. Khanna: None. K. Anukam: None. L. Chow: None. E. Brydges: None. S.L. Liu: Consultant; Self; Novo Nordisk Inc., Sanofi. Research Support; Self; Physicians' Services Inc. Foundation. J. Mahon: None. T.R. Joy: Speaker's Bureau; Self; Amgen Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Amgen Inc., AstraZeneca, Novo Nordisk Inc. R.M. McManus: None.

BACKGROUND: Use of immune checkpoint inhibitors (ICPIs) for treating advanced malignancies has uncovered various endocrinopathies, often as immune-related adverse events (irAEs). CASE: A 72-year-old man with metastatic melanoma presented with a 1-week history of fatigue, dizziness, nausea and vomiting. He received ipilimumab, a CTLA-4 inhibitor, with nivolumab, a PD-1 inhibitor, for two months, then nivolumab alone for the past four months. On presentation, blood pressure was 94/67 mmHg; serum sodium was 124 mEq/L (reference range 136-142 mEq/L). Given a high suspicion for secondary adrenal insufficiency, random afternoon serum cortisol and ACTH levels were drawn immediately, and he was managed empirically with dexamethasone. Serum cortisol returned at 1.1 µg/dL (reference range: 2-14 µg/dL) with undetectable ACTH level, consistent with the diagnosis. No other pituitary hormonal insufficiencies were present. Magnetic resonance imaging revealed stable brain metastases, no hypophysitis and normal-sized pituitary fossa. He was discharged on prednisone 7.5 mg daily and subsequently transitioned to hydrocortisone 20 mg daily. During 18 months of follow-up, no recovery of the pituitary-adrenal axis and no further pituitary hormonal insufficiencies have occurred. DISCUSSION: Nivolumab and ipilimumab are ICPIs, augmenting T-cell function against tumor cells, and potentially against non-cancerous cells, the latter leading to irAEs, including various endocrinopathies. To date, there are 20 case reports of isolated secondary adrenal insufficiency without radiographic evidence of hypophysitis, as in our case. Median onset occurred at 5.1 months after initial ICPI exposure, with 15% of cases associated with a CTLA-4 inhibitor, 80% of cases associated with a PD-1 inhibitor, and 1 case of combination therapy. Prognosis for recovery is poor for adrenal insufficiency, ranging 0 to 19%, unlike other endocrinopathies such as secondary hypothyroidism or hypogonadism. Our case demonstrates that although symptoms of nausea, vomiting, and fatigue are common among oncology patients, clinical suspicion for adrenal insufficiency should remain high among patients receiving ICPIs.

Pregnancies complicated by diabetes are increasingly frequent. The Endocrine and Pregnancy Clinic [EPC] at St Joseph’s Health Care London is the stable, local provider of all outpatient pregnancy diabetes care, thereby providing an opportunity to document patient characteristics with time. Methods EPC charts were reviewed for: 2000-2002; 2010-2012; 2014-2016 documenting DM type (T1DM, T2DM, GDM); age; weight; year/week of DM diagnosis; medication/pump use; A1C. Continuous results were analyzed by one-way analysis of variance (ANOVA); non-parametric results were analyzed by Chi-square testing; p Results Total EPC DM women were: 2000-2002: 408; 2010-2012: 571; 2014-2016: 813. GDM women represented 72.8% of EPC patients in 2001-2002 and 88.4% in 2014-2016. Weights and oral medication use increased with time for women with GDM, while insulin use decreased. Pump use in women with T1DM increased by 2010-2012 and 2014-2016 while A1C decreased significantly comparing first to last visits within each time interval. Numbers of women with T2DM increased significantly but weight at first clinic visit was lower over time, while A1C decreased significantly when comparing first to last visits within each time interval. Discussion/Conclusions EPC volumes doubled from 2000 to 2016 with no increase in background deliveries, predominantly due to increased numbers of women GDM, along with a small increase in women with T2DM. These findings may help inform decisions around health care planning and resource allocation.

Members of the College of Physicians and Surgeons of Ontario Endocrinology and Metabolism Peer Review Network have been involved in a quality improvement project to help standardize the peer assessment of physicians practicing in endocrinology and metabolism. This has included developing state-of-the-art summaries of common endocrine problems by Canadian experts in endocrinology and metabolism. These tools have been developed in response to the educational needs, as identified by peer reviewers, of practicing endocrinologists in Ontario. These pedagogical tools aim not only to standardize the documentation of the clinical performance of endocrinologists but also to make the process more transparent and to improve the quality of patient care in Ontario. This article summarizes the project and also provides the tools developed for the endocrinology and metabolism section of the College of Physicians and Surgeons of Ontario.

Statin-related myalgia compared with myalgia due to other causes is difficult to distinguish and may often lead to statin discontinuation. This proof-of-concept study involved patients who previous...

AIM To evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of nonalcoholic steatohepatitis (NASH). METHODS Twelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy. RESULTS Sitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% ± 0.4% vs 7.9% ± 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 ± 3.5 μg/mL vs 3.9 ± 2.7 μg/mL, P = 0.06) and triglyceride levels (1.26 ± 0.43 mmol/L vs 2.80 ± 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mmol/L, P = 0.19) but did trend towards improved adiponectin levels only (mean difference, 0.60 μg/mL, P = 0.095). No significant changes in anthropometrics, liver enzymes, other adipocytokines, lipid profile, thrombosis parameters, or adipose distribution were demonstrated. The MRI IDEAL procedure correlated well with steatosis scores obtained on liver biopsy in both groups at baseline and post-treatment, and the Spearman correlation coefficients ranged from r = 0.819 (baseline) to r = 0.878 (post-treatment), P = 0.002. CONCLUSION Sitagliptin does not improve fibrosis score or NAS after 24 wk of therapy. The MRI IDEAL technique may be useful for non-invasive measurement of hepatic steatosis.

Elevated low density lipoprotein cholesterol (LDL-C) levels have been associated with an increased risk for cardiovascular disease (CVD). Despite a 25-30% reduction in CVD risk with LDL-C reducing strategies, there is still a significant residual risk. Moreover, achieving target LDL-C values in individuals at high CVD risk is sometimes limited because of tolerability and/or efficacy. Thus, novel therapeutic agents are currently being developed to lower LDL-C levels further. This review will highlight some of these therapeutic agents including anti-sense oligonucleotides focused on apolipoprotein B, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, microsomal triglyceride transfer protein inhibitors, and thyromimetics. For each therapeutic class, an overview of the mechanism of action, pharmacokinetic data, and efficacy/safety evidence will be provided.

Niacin, or water-soluble vitamin B(3), when given at pharmacologic doses, is a powerful lipid-altering agent. This drug, which lowers the levels of atherogenic, apolipoprotein-B-containing lipoproteins, is one of few medications that can raise the levels of atheroprotective HDL cholesterol. Niacin also has beneficial effects on other cardiovascular risk factors, including lipoprotein(a), C-reactive protein, platelet-activating factor acetylhydrolase, plasminogen activator inhibitor 1 and fibrinogen. Many clinical trials have confirmed the lipid effects of niacin treatment; however, its effects on cardiovascular outcomes have been called into question owing to the AIM-HIGH trial, which showed no benefit of niacin therapy on cardiovascular endpoints. Furthermore, use of niacin has historically been limited by tolerability issues. In addition to flushing, worsened hyperglycaemia among patients with diabetes mellitus has also been a concern with niacin therapy. This article reviews the utility of niacin including its mechanism of action, clinical trial data regarding cardiovascular outcomes, adverse effect profile and strategies to address these effects and improve compliance.

Inhibition of cholesteryl ester transfer protein (CETP), a key protein involved in reverse cholesterol transport, can lead to increases in high-density lipoprotein cholesterol (HDL-C) levels and thus, is under evaluation as an antiatherogenic strategy. Several CETP inhibitors have been under development including anacetrapib, dalcetrapib, and torcetrapib. To date, anacetrapib demonstrates the greatest HDL-C raising and low-density lipoprotein cholesterol (LDL-C) lowering potential. Phase I and phase II trials with anacetrapib have revealed that anacetrapib is well-tolerated and does not seem to possess the pressor effects associated with torcetrapib. This article will briefly review the HDL-C raising through CETP inhibition as an antiatherogenic strategy with a specific focus on anacetrapib.

Evaluation of: Murray A, Cluett C, Bandinelli S et al.: Common lipid-altering gene variants are associated with therapeutic intervention thresholds of lipid levels in older people. Eur. Heart J. 30, 1711–1719 (2009). Increased plasma LDL-C and triglyceride concentrations and reduced plasma HDL-C concentrations are associated with increased cardiovascular disease risk. Recent genome-wide association studies have identified numerous genetic variants – single nucleotide polymorphisms (SNPs) – influencing plasma LDL-C, HDL-C and triglyceride concentrations. Murray et al. evaluated approximately 600 older people (≥65 years; 43% males) from the Invecchiare in Chianti, Aging in the Chianti Area (InCHIANTI) study and genotyped 21 lipid-associated SNPs identified from early genome-wide association studies. While individual SNP effects on plasma lipid concentrations were small, effect sizes were somewhat larger when SNPs were combined into an allele score. The extreme quartiles of these scores were significantly as...

BACKGROUND: 5-hydroxyindoleacetic acid (5-HIAA) excretion is commonly measured for biochemical detection of carcinoid tumours. A 77-year-old woman was referred for elevated 24 h urine 5-HIAA excretion (510 μmol/day; normal is less than 45 μmol/day) and serum chromogranin A (CgA) (72.1 U/L; normal is less than 18 U/L), both subsequently normalized after discontinuation of 5-hydroxytryptophan (5-HTP). 5-HTP, a precursor of serotonin, is not commonly listed as a substance that increases 5-HIAA levels in urine. The effect of 5-HTP on CgA has not been previously described.OBJECTIVES: To determine whether, and to what extent, oral 5-HTP increases urine 5-HIAA excretion and serum CgA levels in healthy volunteers.PATIENTS AND METHODS: A randomized, prospective, double-blind, placebo-controlled crossover study, with a four-day washout period, was performed in a general community setting. Eight healthy subjects aged 22 to 58 years were recruited by advertising. Bedtime ingestion of 5-HTP 100 mg/day was compared with placebo ingestion for 10 days. Twenty-four hour urine excretion of 5-HIAA and serum CgA were the main outcome measures.RESULTS: Median (range) urinary 5-HIAA excretion was 204 μmol/day (22 μmol/day to 459 μmol/day) during 5-HTP intake, compared with 18 μmol/day (12 μmol/day to 36 μmol/day) during placebo intake (P=0.017). 5-HTP did not affect clinical symptoms or serum CgA levels.CONCLUSIONS: Oral 5-HTP increases urinary 5-HIAA excretion with considerable interindividual variation. In a small number of subjects, oral 5-HTP did not affect serum CgA levels. Therefore, increased 5-HIAA levels with normal CgA levels may suggest 5-HTP ingestion. The use of over-the-counter 5-HTP should be excluded as the cause of increased urinary 5-HIAA levels before initiating diagnostic tests to search for a carcinoid tumour. 5-HTP should be added to popular references as a substance that may cause increased 5-HIAA excretion.

The lipodystrophies are characterized by loss of adipose tissue in some anatomical sites, frequently with fat accumulation in nonatrophic depots and ectopic sites such as liver and muscle. Molecularly characterized forms in- clude Dunnigan-type familial partial lipodystrophy (FPLD), partial lipodystrophy with mandibuloacral dysplasia (MAD), Berardinelli-Seip congenital generalized lipodystrophy (CGL), and some cases with Barraquer-Simons acquired partial lipodystrophy (APL). The associated mutant gene products include1) nuclear lamin A in FPLD type 2 and MAD type A; 2) nuclear lamin B2 in APL; 3) nuclear hormone receptor peroxisome proliferator-activated receptor g in FPLD type 3; 4 ) lipid biosynthetic enzyme 1-acylglycerol-3- phosphate O-acyltransferase 2 in CGL type 1; 5 ) integral endoplasmic reticulum membrane protein seipin in CGL type 2; and 6 ) metalloproteinase ZMPSTE24 in MAD type B. An unresolved question is whether metabolic disturbances are secondary to adipose repartitioning or result from a direct effect of the mutant gene product. Careful analysis of clinical, biochemical, and imaging phenotypes, using an approach called "phenomics," reveals differences between genetically stratified subtypes that can be used to guide basic experiments and to improve our understanding of common clinical entities, such as metabolic syndrome or the partial lipodystrophy syndrome associated with human immuno- deficiency virus infection.—Hegele, R. A., T. R. Joy, S. A. Al-Attar, and B. K. Rutt. Lipodystrophies: windows on adi- pose biology and metabolism.J.LipidRes. 2007.48: 1433-1444.

Sitosterolemia is a rare autosomal recessive disorder of lipoprotein metabolism characterized by xanthomas and increased plasma concentrations of plant sterols, such as sitosterol. Causative mutations occur in either the ABCG5 or ABCG8 gene, each of which encodes a sterol half-transporter expressed in the intestine. We report five Canadian subjects with nonsense mutations in these half-transporters: four related Caucasian subjects were homozygous for the ABCG8 S107X mutation, and one unrelated Japanese-Canadian subject was homozygous for a complex insertion/deletion (I/D) mutation in ABCG5 exon 3. A female subject with each mutation was symptomatic with coronary atherosclerosis: a 5-year-old ABCG8 S107X homozygote and a 75-year-old ABCG5 exon 3 I/D homozygote; these represent the extreme ends of the spectrum of vascular involvement in sitosterolemia. The largest reductions in plasma concentrations of sitosterol and LDL-cholesterol were seen with ezetimibe or bile acid sequestrant treatment, and less dramatic reductions were seen with statin drug treatment. These findings extend the range of clinical phenotypes in sitosterolemia caused by nonsense mutations in either ABCG5 or ABCG8.

Stroke is a major cause of adult neurological disability and mortality, and is a complex heterogeneous phenotype culminating from a range of pathogenic mechanisms. In this chapter, we discuss advances and complications in the genomic analysis of stroke. Monogenic forms of stroke are rare in the population but can provide insight into pathogenic mechanisms. The genomic analysis of common complex stroke has shifted from candidate gene association studies to genome-wide association studies. Discovery of genes contributing to stroke risk will provide insights into the molecular disease processes and opportunities to identify high-risk patients for risk reduction strategies.

Reduction in low-density lipoprotein cholesterol (LDL-C) levels has been associated with a 25–30% reduction in cardiovascular disease risk. However, there still remains a significant and quantifiable risk. Since epidemiologic data have demonstrated that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with an increased risk for cardiovascular disease, novel therapeutic agents are currently being developed to either raise HDL-C levels or enhance HDL functionality. This review will highlight some of these therapeutic agents including cholesteryl ester transfer protein inhibitors, apolipoprotein A-I mimetics, RVX-208, and apolipoprotein A-I based infusion therapies. For each therapeutic class, an overview of the mechanism of action, pharmacokinetic data, and efficacy/safety evidence will be provided.

Bernard Lonergan's cognitive theory challenges us to raise questions about both the cognitive process through which obesity is perceived as a behaviour change issue and the objectivity of such a moral judgment. Lonergan's theory provides the theoretical tools to affirm that anti-fat discrimination, in the United States of America and in many industrialized countries, is the result of both a group bias that resists insights into the good of other groups and a general bias of anti-intellectualism that tends to set common sense against insights that require any thorough scientific analyses. While general bias diverts the public's attention away from the true aetiology of obesity, group bias sustains an anti-fat culture that subtly legitimates discriminatory practices and policies against obese people. Although anti-discrimination laws may seem to be a reasonable way of protecting obese and overweight individuals from discrimination, obesity bias can be best addressed by reframing the obesity debate from an environmental perspective from which tools and strategies to address both the social and individual determinants of obesity can be developed. Attention should not be concentrated on individuals' behaviour as it is related to lifestyle choices, without giving due consideration to the all-encompassing constraining factors which challenge the social and rational blindness of obesity bias.

Purpose: To validate iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) for adipose tissue volume quantification. IDEAL allows MRI images to be produced only from adipose-containing tissues; hence, quantifying adipose tissue should be simpler and more accurate than with current methods. Materials and Methods: Ten healthy controls were imaged with 1.5 Tesla (T) Spin Echo (SE), 3.0T T1-weighted spoiled gradient echo (SPGR), and 3.0T IDEAL-SPGR. Images were acquired from the abdomen, pelvis, mid-thigh, and mid-calf. Mean subcutaneous and visceral adipose tissue volumes were compared between the three acquisitions for each subject. Results: There were no significant differences (P > 0.05) between the three acquisitions for subcutaneous adipose tissue volumes. However, there was a significant difference (P = 0.0002) for visceral adipose tissue volumes in the abdomen. Post hoc analysis showed significantly lower visceral adipose tissue volumes measured by IDEAL versus 1.5T (P < 0.0001) and 3.0T SPGR (P < 0.002). The lower volumes given by IDEAL are due to its ability to differentiate true visceral adipose tissue from other bright structures like blood vessels and bowel content that are mistaken for adipose tissue in non-fat suppressed images. Conclusion: IDEAL measurements of adipose tissue are equivalent to established 1.5T measurement techniques for subcutaneous depots and have improved accuracy for visceral depots, which are more metabolically relevant. J. Magn. Reson. Imaging 2011;. © 2011 Wiley-Liss, Inc.

A wide range of lipodystrophy syndromes exist, each with varying clinical presentations, and yet cumulatively they underscore the importance of adipocyte biology in human metabolism. Loss of the ability to retain excess lipids in "classical" adipose tissue stores can lead to the overdevelopment of ectopic fat stores, often creating severe perturbations of both glucose and lipid homeostasis. Linkage analysis and candidate sequencing efforts have successfully identified responsible mutations for multiple forms of lipodystrophy. Recently, the reduction in the cost of DNA sequencing has resulted in discovery of many novel mutations within both known and novel loci. In this review, we present the steps involved in clinical characterization of a suspected lipodystrophy case, an overview of the clinical manifestations, molecular findings, and pathogenic basis of different forms of lipodystrophy, a discussion of therapeutic options for lipodystrophy patients, and an examination of genetic advances that will be used to identify additional pathogenic mechanisms.

A wide range of lipodystrophy syndromes exist, each with varying clinical presentations, and yet cumulatively they underscore the importance of adipocyte biology in human metabolism. Loss of the ability to retain excess lipids in “classical” adipose tissue stores can lead to the overdevelopment of ectopic fat stores, often creating severe perturbations of both glucose and lipid homeostasis. Linkage analysis and candidate sequencing efforts have successfully identified responsible mutations for multiple forms of lipodystrophy. Recently, the reduction in the cost of DNA sequencing has resulted in discovery of many novel mutations within both known and novel loci. In this review, we present the steps involved in clinical characterization of a suspected lipodystrophy case, an overview of the clinical manifestations, molecular findings, and pathogenic basis of different forms of lipodystrophy, a discussion of therapeutic options for lipodystrophy patients, and an examination of genetic advances that will be used to identify additional pathogenic mechanisms.

PURPOSE OF REVIEW: Because high-density lipoprotein cholesterol (HDL-C) levels are inversely related to cardiovascular disease (CVD), raising HDL-C levels would seem intuitively valuable. However, the recent failure of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib to decrease CVD has raised doubts regarding HDL-C raising in general and CETP inhibition in particular for CVD prevention. We briefly discuss the complexity of HDL metabolism, caveats of CETP inhibition, possible mechanisms for torcetrapib's failure, and the potential utility of other CETP inhibitors. RECENT FINDINGS: Torcetrapib likely failed because of off-target effects, since other CETP inhibitors, such as dalcetrapib (JTT-705/R1658) or anacetrapib (MK-0859), do not increase blood pressure, a specific pressor effect of tocetrapib that appears to be CETP-independent. In small human trials of short duration, anacetrapib and dalcetrapib appear to improve the lipoprotein profile without obvious adverse effects, so far. SUMMARY: The relationship between HDL metabolism, pharmacologic CETP inhibition, and atherosclerosis requires further elucidation. There seems to be sufficient evidence that evaluation of CETP inhibitors such as dalcetrapib and anacetrapib should proceed, if cautiously, since it remains uncertain whether the increased CVD risk with torcetrapib was related to agent-specific off-target effects or more generally to CETP inhibition as a mechanism to raise HDL.

Statin-related myopathy is a clinically important cause of statin intolerance and discontinuation. The spectrum of statin-related myopathy ranges from common but clinically benign myalgia to rare but life-threatening rhabdomyolysis. Observational studies suggest that myalgia can occur in up to 10% of persons prescribed statins, whereas rhabdomyolysis continues to be rare. The mechanisms of statin-related myopathy are unclear. Options for managing statin myopathy include statin switching, particularly to fluvastatin or low-dose rosuvastatin; nondaily dosing regimens; nonstatin alternatives, such as ezetimibe and bile acid-binding resins; and coenzyme Q10 supplementation. Few of these strategies have high-quality evidence supporting them. Because statin-related myopathy will probably become more common with greater numbers of persons starting high-dose statin therapy and the increasing stringency of low-density lipoprotein cholesterol level targets, research to better identify patients at risk for statin myopathy and to evaluate management strategies for statin-related myopathy is warranted.

The objective of the study was to determine correlations between magnetic resonance imaging (MRI) measures of truncal adiposity (trunk fat percentage [TrF %(MRI)], visceral adipose tissue [VAT], and subcutaneous abdominal adipose tissue [SAT]), simple clinical measures (body mass index [BMI], waist circumference [WC], and waist-to-hip ratio [WHR]), and bioelectrical impedance analysis (BIA)-derived measures (total fat percentage [TF %] and TrF %(BIA)) in female patients with familial partial lipodystrophy (FPLD). Our secondary aim was to generate and cross-validate predictive equations for VAT and SAT using these simple clinical and BIA-derived variables. Measures of truncal adiposity were measured using 1.5-T MRI (VAT, SAT, and TrF %(MRI)) and Tanita (Tokyo, Japan) 8-electrode body composition analyzer BC-418 (TrF %(BIA)) in 13 female FPLD patients. Pearson correlation coefficients were determined among the various adiposity parameters (BMI, WC, WHR, SAT, VAT, TrF %(MRI), TrF %(BIA), and TF %). Equations to estimate VAT and SAT were determined among 6 of the 13 FPLD subjects using multilinear regression analysis, and the best equations were then cross-validated in the remaining 7 subjects. Variables entered into the model included age, BMI, WC, WHR, TrF %(BIA), and TF %. The TrF %(MRI) showed moderate correlation (r = 0.647, P = .02) with the TrF %(BIA), but the discrepancy between the 2 variables increased with increasing truncal adiposity. The strongest correlate for TrF %(MRI) was BMI (r = 0.886, P < .0001). Visceral adipose tissue was poorly associated with simple clinical measures of BMI, WC, and WHR, but was inversely correlated with TF %, TrF %(BIA), and SAT. The TF % was the strongest correlate for both SAT and VAT. Thus, the best regression equation for VAT included age, BMI, WC, and TF % (R(2) = 1.0), whereas that for SAT only included TF % (R(2) = 0.75). The corresponding standard error of the estimate for the predictive equations was approximately 0.03 % and 18.5 % of the mean value of VAT and SAT, respectively. In the cross-validation study, differences between predicted and observed values of SAT were larger than those of VAT. We conclude that, among female FPLD patients, (1) no simple clinical anthropometric measure correlates well with VAT, whereas BMI correlates well with SAT; (2) BIA measure of TF % most strongly correlated with both VAT and SAT; and (3) based on the cross-validation study, VAT but not SAT could be more reliably estimated using the regression equations derived.

Objective: To compare the risk of having polycystic ovary syndrome (PCOS) or ovarian cysts among women with genetically confirmed familial partial lipodystrophy (FPLD) with that in the general population of healthy women. Methods: Twenty-five women with FPLD who were 18 to 80 years old were interviewed regarding a history of PCOS or ovarian cysts (composite primary outcome) as well as for secondary outcomes of interest including men strual irregularities, hirsutism, gynecologic surgical proce dures, and fertility or obstetric complications. From the 2005 National Ambulatory Medical Care Survey, 3,326 women, aged 18 to 80 years (control subjects), were assessed for the presence of the primary outcome based on appropriate International Classification of Diseases, Ninth Revision, Clinical Modification codes. Results: Four of the 25 patients with FPLD (16%) had a history of PCOS or ovarian cysts, in comparison with 14 of the 3,326 control subjects (0.42%), resulting in an age- and body mass index-adjusted odds ratio of 40.6 (95% confidence interval, 12.1 to 136.7; P

Many patients at high risk for coronary heart disease (CHD) fail to reach target lipid levels with currently available medications, and a small but clinically relevant proportion of patients experience adverse effects. Thus, additional pharmaceutical strategies are required to fill these gaps in efficacy and tolerability.To provide an overview of both current and emerging antidyslipidemic drugs.For the current antidyslipidemic drugs, we focus primarily on statins, bile acid sequestrants, fibrates, ezetimibe, and niacin. Emerging antidyslipidemic drugs herein discussed were identified by searching the Pharmaprojects database for 'hypercholesterolemia drugs' (Phase II or Phase III), 'HDL-based therapies', and 'PCSK9 inhibition'.Combinations of currently existing medications are most easily applicable. Meanwhile, strategies to raise HDL-C rely on a deep understanding of the complexity of HDL metabolism. Furthermore, novel approaches to further reduce LDL-C warrant careful evaluation of benefit-risk ratio. Finally, the medical community will have to rely on late-phase CHD outcome studies as the final arbiter of clinical application for any new antidyslipidemia treatment.

Metabolic syndrome (MetS) is a common phenotype, affecting about 24% of the US population. It is associated with an increased risk for type 2 diabetes and cardiovascular disease. Although there is no universally accepted definition for MetS, affected individuals commonly have a cluster of features, including abdominal obesity, hypertension, dyslipidemia, and dysglycemia. Recently, there has been extensive interest in potential genetic contributions to MetS. At present, no single gene or cluster of genes has been consistently replicated for MetS among different populations, likely due to the complex interplay between gene and environment necessary for expression of this phenotype. We review recent studies regarding the genetic contributions to MetS.

The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein inhibitor torcetrapib has led to considerable doubt about the value of raising high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These results have underscored the intricacy of HDL metabolism, with functional quality perhaps being a more important consideration than the circulating quantity of HDL. As a result, HDL-based therapeutics that maintain or enhance HDL functionality warrant closer investigation. In this article, we review the complexity of HDL metabolism, discuss clinical-trial data for HDL-raising agents, including possible reasons for the failure of torcetrapib, and consider the potential for future HDL-based therapies.

Background Alstrom syndrome (AS) is a rare autosomal recessive disease characterized by multiorgan dysfunction. The key features are childhood obesity, blindness due to congenital retinal dystrophy, and sensorineural hearing loss. Associated endocrinologic features include hyperinsulinemia, early-onset type 2 diabetes, and hypertriglyceridemia. Thus, AS shares several features with the common metabolic syndrome, namely obesity, hyperinsulinemia, and hypertriglyceridemia. Mutations in the ALMS1 gene have been found to be causative for AS with a total of 79 disease-causing mutations having been described. Case presentation We describe the case of a 27-year old female from an English (Caucasian) kindred. She had been initially referred for hypertriglyceridemia, but demonstrated other features suggestive of AS, including blindness, obesity, type 2 diabetes, renal dysfunction, and hypertension. DNA analysis revealed that she is a compound heterozygote with two novel mutations in the ALMS1 gene – H3882Y and V424I. Examination of her family revealed that her phenotypically unaffected mother and younger sister also had heterozygous mutations in the ALMS1 gene. In addition to presenting these novel molecular findings for AS, we review the clinical and genetic features of AS in the context of our case. Conclusion Two novel mutations in the ALMS1 gene causative for AS have been reported here, thereby increasing the number of reported mutations to 81 and providing a wider basis for mutational screening among affected individuals.

Good nutrition plays an important role in the optimal growth, development, health and well-being of individuals in all stages of life. Healthy eating can reduce the risk of chronic diseases, such as heart disease, stroke, diabetes and some types of cancer. However, the capitalist mindset that shapes the food environment has led to the commoditization of food. Food is not just a marketable commodity like any other commodity. Food is different from other commodities on the market in that it is explicitly and intrinsically linked to our human existence. While possessing another commodity allows for social benefits, food ensures survival. Millions of people in United States of America are either malnourished or food insecure. The purpose of this paper is to present a critique of the current food system using four meanings of the common good--as a framework, rhetorical device, ethical concept and practical tool for social justice. The first section of this paper provides a general overview of the notion of the common good. The second section outlines how each of the four meanings of the common good helps us understand public practices, social policies and market values that shape the distal causal factors of nutritious food inaccessibility. We then outline policy and empowerment initiatives for nutritious food access.

CONFLICTS OF INTEREST: Dr RA Hegele (Advisory Boards and Speakers Bureaus: Pfizer, Merck Frosst, Schering, AstraZeneca, Boehringer Ingelheim, Solvay and Kowa). Dr T Joy (Speakers Bureaus: Merck Frosst, Schering).

Adipose distribution is a useful tool for cardiovascular risk stratification when compared to body mass index (BMI) alone. We sought to compare intra-thoracic fat distribution in patients with or without metabolic syndrome (MetS), and to identify differences in those with and without evidence of prior myocardial infarction (MI), as determined by delayed enhancement (DE) MRI.