The Association between Metabolic Syndrome and Multiple Myeloma.

Multiple myeloma (MM) is a haematological malignancy arising from monoclonal proliferation of plasma cells in the bone marrow, resulting in the presence of paraproteins or M-protein in serum. The involvement of paraproteins produced by malignant plasma cells in the development of hyperlipidaemia and low-HDL cholesterol has been described, as has an association with MM and obesity, hypertension, and type 2 diabetes mellitus, and insulin resistance, that is, features of the metabolic syndrome (MS). There is an association between MS components, inflammatory cytokines, and the development of MM, and some drugs used in the treatment of MS such as statins and metformin may improve outcomes in MM.

Review of referral criteria to lipid clinics and outcomes of treatment in four UK centres.

BACKGROUND: Little data exist on the referral patterns and effectiveness of lipid clinics. METHODS: An audit was conducted in four clinics of 100 consecutive referrals each. Data were recorded on referral criteria, cardiovascular disease (CVD) risk factors, drug history, investigations, diagnoses, therapies, results and referrals. RESULTS: Patients were aged 56 ± 14 years, 47% were male and 87% were primary prevention. Risk factors included smoking (16%), type 2 diabetes (13%) and hypertension (13%). Referrals were made for hypercholesterolaemia (68%), diagnosis of FH (31%), statin intolerance (23%) and hypertriglyceridaemia (23%). Initial total cholesterol (TC) was 7.65 ± 2.64 mmol/L, triglycerides (TG) 2.17 (0.41-76.9 mmol/L) mmol/L, HDL-C 1.53 ± 0.71 mmol/L, LDL-C 4.57 ± 1.66 mmol/L with non-HDL-C 5.90 ± 2.09 mmol/L. Criteria for FH were met in 21% with genetic testing in 13% and lipid cascade testing in 30% of index cases. Triglycerides >20 mmol/L were present in 4%. The diagnosis was changed in 21%: hypercholesterolaemia (7%), mixed hyperlipidaemia (7%) and hypertriglyceridaemia (7%). Hepatic steatosis was identified in 14.5%. Lipoprotein(a) levels >125 nmol/L occurred in 41% in one clinic. Therapy changes included altered statins (40%), addition of a fibrate (11%) or ezetimibe (8%). These reduced TC by 1.92 mmol/L (19%; P = 0.0001), LDL-C 1.07 mmol/L (15%; P = 0.02), non-HDL-C 1.50 mmol/L (16%; P < 0.001), and TG 2.3 (-4 to 38) mmol/L (16%; P < 0.001) with 11% extra achieving TG <5 mmol/L while HDL-C increased by 7% (P = 0.37). CONCLUSIONS: Lipid clinics have diverse functions including diagnosis of FH, managing severe hypercholesterolaemia, mixed hyperlipidaemia and statin intolerance. Effectiveness criteria of average reductions of 1.5 mmol/L in TC or non-HDL-C, 1 mmol/L in LDL-C and 2 mmol/L in TG would be reasonable for newly referred patients.

Pro-protein subtilisin kexin-9 (PCSK9) inhibition in practice: lipid clinic experience in 2 contrasting UK centres.

BACKGROUND: Prescribing criteria have been suggested for proprotein convertase subtilisin kexin-9 (PCSK-9) inhibitors but few studies exist of their real-world effectiveness. METHODS: This study audited PCSK-9 inhibitor therapy in 105 consecutive patients from two hospital centres-a university hospital (UH; n = 70) and a district general hospital (DGH; n = 35). Baseline characteristics including cardiovascular disease risk factors, NICE qualification criteria, efficacy and side effects were assessed. RESULTS: Baseline LDL-C levels were similar in both centres. NICE criteria were met for 2.05 items in the whole study (UH patients 1.7 and DGH patients 2.7). District general hospital patients were more likely to have familial hypercholesterolaemia (89 vs 69%; P = .02); intolerance to statins (94 vs 52%; P < .001) and polyvascular disease (42% vs 17%; P = .005). Prescriptions (evolocumab 73%; alirocumab 23%) were collected by 76% of patients (UH 64% vs DGH 100%). Therapy was discontinued by time of review in 15% of patients (UH 7% vs DGH 25%; P = .02). In adherent patients PCSK-9 inhibitor treatment reduced TC by 28% (2.24 ± 2.39 mmol/L; P < .001) and LDL-C by 49% (2.10 ± 1.33 mmol/L; P < .001). A LDL-C < 2.5 mmol/L was achieved in 30% of patients and <2.0 mmol/L in 20%. PCSK-9 therapy was effective and safe in patients with increased lipoprotein (a), diagnosed muscle diseases (including myopathies and muscular dystrophy) or poststatin rhabdomyolysis, nephrotic syndrome or HIV disease. Mixed results were obtained in patients with significant mixed hyperlipidaemia. CONCLUSIONS: This study suggests that PCSK-9 inhibitors are effective but that prescriptions should not be changed to long-term delivery until patients have been reviewed and shown to be adherent.

Causes of hypoamylasaemia in a hospital population.

AIMS: We noted serum amylase activity results in our laboratory that fell below the lower reference limit, although there was no obvious explanation for this and the literature on this topic is relatively sparse. METHODS: We studied hospital laboratory requests and reports of individuals showing hypoamylasaemia over a one-year period. RESULTS: We report one of the few studies to look at hypoamylasaemia in a hospital population. We found that 5.4% of the hospital serum amylase activity results were below the reference range quoted by our laboratory. CONCLUSIONS: Some of the associations we observed with hypoamylasaemia were diabetes mellitus, cystic fibrosis, hypertriglyceridaemia and use of the antibiotic gentamicin. We suggest that clinicians and laboratories should be aware of the causes of hypoamylasaemia to aid interpretation of abnormally low amylase activity in their patients.

Lipid clinic experience with bempedoic acid in three UK centres.

OBJECTIVE: Novel lipid-lowering therapies are being introduced. Few studies exist of the real-world effectiveness of adenosine-tri-phosphate citrate lyase inhibition with bempedoic acid. METHODS: This study audited bempedoic acid therapy in 216 consecutive patients from three hospital centres - a university hospital (n = 77) and two district general hospitals (n = 106 and 33). Cardiovascular disease (CVD) risk factors, prescription qualification criteria, efficacy and adverse effects were assessed. RESULTS: The population was aged 65.9 ± 11.0 years, 42% were male, 25% had type 2 diabetes, and 31% had familial hypercholesterolaemia. CVD was present in 19% and multibed vascular disease in 8%. Statin intolerance was reported in 92%. Bempedoic acid reduced total cholesterol by 1.58 ± 1.44 mmol/L (20%), LDL-C by 1.37 ± 1.31 mmol/L (27%), triglycerides by 0.22 mmol/L (2%) with an 0.06 mmol/L (1%) increase in HDL-C after 22 ± 9 months follow-up. An LDL-C <2.5 mmol/L was achieved in 40% and <2 mmol/L in 20%. Efficacy (r2 = .33) was predicted by baseline LDL-C (ß = .54; p <.001). No significant changes were seen in transaminases, creatinine, creatine kinase, urate or HbA1c. Treatment was discontinued by 33% of patients and occurred due to myalgia (43%), lack of efficacy (16%) and gastrointestinal adverse effects (15%). No cases of gout were observed. In a logistic regression only the number of previous drug classes not tolerated (ß = 1.60; p = .009) was a contributing factor to discontinuation. CONCLUSION: This audit suggests that bempedoic acid therapy is effective but that adverse effects and discontinuation are common. This suggests nocebo effects might be generalizable to all lipid-lowering drug therapies in susceptible individuals.

CDKN2B expression in adipose tissue of familial combined hyperlipidemia patients.

The purpose of this study was to determine the core biological processes perturbed in the subcutaneous adipose tissue of familial combined hyperlipidemia (FCHL) patients. Annotation of FCHL and control microarray datasets revealed a distinctive FCHL transcriptome, characterized by gene expression changes regulating five overlapping systems: the cytoskeleton, cell adhesion and extracellular matrix; vesicular trafficking; lipid homeostasis; and cell cycle and apoptosis. Expression values for the cell-cycle inhibitor CDKN2B were increased, replicating data from an independent FCHL cohort. In 3T3-L1 cells, CDKN2B knockdown induced C/EBPα expression and lipid accumulation. The minor allele at SNP site rs1063192 (C) was predicted to create a perfect seed for the human miRNA-323b-5p. A miR-323b-5p mimic significantly reduced endogenous CDKN2B protein levels and the activity of a CDKN2B 3'UTR luciferase reporter carrying the rs1063192 C allele. Although the allele displayed suggestive evidence of association with reduced CDKN2B mRNA in the MuTHER adipose tissue dataset, family studies suggest the association between increased CDKN2B expression and FCHL-lipid abnormalities is driven by factors external to this gene locus. In conclusion, from a comparative annotation analysis of two separate FCHL adipose tissue transcriptomes and a subsequent focus on CDKN2B, we propose that dysfunctional adipogenesis forms an integral part of FCHL pathogenesis.

Patient accounts of diagnostic testing for familial hypercholesterolaemia: comparing responses to genetic and non-genetic testing methods.

BACKGROUND: Continuing developments in genetic testing technology together with research revealing gene-disease associations have brought closer the potential for genetic screening of populations. A major concern, as with any screening programme, is the response of the patient to the findings of screening, whether the outcome is positive or negative. Such concern is heightened for genetic testing, which it is feared may elicit stronger reactions than non-genetic testing. METHODS: This paper draws on thematic analysis of 113 semi-structured interviews with 39 patients being tested for familial hypercholesterolaemia (FH), an inherited predisposition to early-onset heart disease. It examines the impact of disease risk assessments based on both genetic and non-genetic information, or solely non-genetic information. RESULTS: The impact of diagnostic testing did not seem to vary according to whether or not genetic information was used. More generally, being given a positive or negative diagnosis of FH had minimal discernible impact on people's lives as they maintained the continuity of their beliefs and behaviour. CONCLUSIONS: The results suggest that concerns about the use of genetic testing in this context are unfounded, a conclusion that echoes findings from studies in this and other health contexts.

The innate immune system and diabetes mellitus: the relevance of periodontitis? A hypothesis.

About a decade ago, a hypothesis was proposed suggesting that the innate immune system, including acute-phase reactants, contribute to the development of T2DM [Type 2 DM (diabetes mellitus)] and the metabolic syndrome. In this model, it was hypothesized that the innate immune system modulates the effects of many factors, including genes, fetal programming, nutrition and aging, upon the later development of metabolic problems associated with insulin resistance. In this present article, we expand this hypothesis by looking at the involvement of periodontitis in DM and its complications. Periodontitis is a common inflammatory process involving the innate immune system and is associated with DM. We will also illustrate how dental disease is important in patients with DM and could be implicated in various diabetic complications.

Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing.

As part of a randomised trial [Genetic Risk Assessment for Familial Hypercholesterolaemia (FH) Trial] of the psychological consequences of DNA-based and non-DNA-based diagnosis of FH, 338 probands with a clinical diagnosis of FH (46% with tendon xanthomas) were recruited. In the DNA-based testing arm (245 probands), using single-strand conformation polymorphism of all exons of the low-density lipoprotein receptor (LDLR) gene, 48 different pathogenic mutations were found in 62 probands (25%), while 7 (2.9%) of the patients had the R3500Q mutation in the apolipoprotein B (APOB) gene. Compared to those with no detected mutation, mean untreated cholesterol levels in those with the APOB mutation were similar, while in those with an LDLR mutation levels were significantly higher (None=9.15+/-1.62 vs LDLR=9.13+/-1.16 vs APOB=10.26+/-2.07 mmol/l p<0.001, respectively). Thirty seven percent of the detected mutations were in exon 3/4 of LDLR, and this group had significantly higher untreated cholesterol than those with other LDLR mutations (11.71+/-2.39 mmol/l vs 9.88+/-2.44 mmol/l, p=0.03), and more evidence of coronary disease compared to those with other LDLR or APOB mutations (36 vs 13% p=0.04). Of the probands with a detected mutation, 54 first-degree relatives were identified, of whom 27 (50%) had a mutation. Of these, 18 had untreated cholesterol above the 95th percentile for their age and gender, but there was overlap with levels in the non-carrier relatives such that 12% of subjects would have been incorrectly diagnosed on lipid levels alone. In the non-DNA-based testing arm (82 probands) only 19 of the 74 relatives identified had untreated cholesterol above the 95th percentile for their age and gender, which was significantly lower (p<0.0005) than the 50% expected for monogenic inheritance. These data confirm the genetic heterogeneity of LDLR mutations in the UK and the deleterious effect of mutations in exon 3 or 4 of LDLR on receptor function, lipids and severity of coronary heart disease. In patients with a clinical diagnosis of FH but no detectable mutation, there is weaker evidence for a monogenic cause compared with relatives of probands with LDLR mutations. This supports the usefulness of DNA testing to confirm diagnosis of FH for the treatment of hyperlipidaemia and for further cascade screening.

Metabolic Syndrome in Long-Term Survivors of Hematopoietic Stem-Cell Transplantation.

Since its introduction more than 50 years ago, hematopoietic stem-cell transplantation (HSCT) has transformed from an inescapably fatal procedure to one where cure from malignant and other nonmalignant hematologic diseases is becoming increasingly common. Nevertheless, longevity is not entirely restored. New causes of mortality have emerged; of particular importance is that of increased cardiovascular disease (CVD), related to metabolic syndrome and its components. Controversy exists over whether the metabolic abnormalities induced are a direct effect of HSCT itself or a consequence of other therapies involved. Analysis of the mechanisms that promote the changes in metabolic components will give insight into future HSCT therapy as well as CVD pathogenesis and prevention.

Percentage of body fat and plasma glucose predict plasma sialic acid concentration in type 2 diabetes mellitus.

Circulating sialic acid is an independent risk factor for cardiovascular disease and is higher in people with type 2 diabetes mellitus. Sialic acid is associated with body mass index, but it is uncertain whether body fat contributes to the higher levels of sialic acid in type 2 diabetes mellitus. Therefore, we have investigated whether the higher levels of sialic acid observed in type 2 diabetes mellitus persist when controlling for fatness. Fasting plasma samples were collected from 24 individuals with type 2 diabetes mellitus and 24 controls. Percentage of body fat was measured by bioelectrical impedance. Plasma sialic acid was quantified by an enzymatic method. Plasma sialic acid was higher in the group with type 2 diabetes mellitus than controls (602 +/- 14 vs 545 +/- 14 mg/L, P = .007). Percentage of body fat was associated with plasma sialic acid concentration in both the control group (r = 0.481, P = .020) and the group with type 2 diabetes mellitus (r = 0.527, P = .007). Fasting glucose was also associated with plasma sialic acid in the group with type 2 diabetes mellitus (r = 0.700, P < .001). Adjustment for percentage of body fat accounted for the higher levels of sialic acid in type 2 diabetes mellitus. Using linear regression, 54.3% of the variation of plasma sialic acid was explained by percentage of body fat and glucose concentrations in the whole group. Seventy-four percent of sialic acid variation was explained by the same model in type 2 diabetes mellitus. In conclusion, this is the first study to show that percentage of body fat predicts plasma sialic acid concentration and contributes toward higher levels of sialic acid in type 2 diabetes mellitus.

Sialic acid: a novel marker of cardiovascular disease?

The global burden posed by cardiovascular disease (CVD), due to a rising incidence of known risk factors, underlines an urgent need to identify other potential risk factors. Sialic acid (SA), an abundant terminal monosaccharide of glycoconjugates, is a possible risk factor for CVD. Although large-scale epidemiological surveys have shown that serum total sialic acid (TSA) is positively associated with mortality from coronary artery disease (CAD) and stroke, studies investigating the correlation between serum TSA and the severity of atherosclerosis are conflicting. Clinical and epidemiological studies indicate that serum TSA is a marker of a sustained inflammatory response in CVD, rather than causal in nature. Data also indicates ethnic variation in baseline TSA. This article reviews current methods for determining serum TSA and evidence supporting serum TSA as a risk factor for CVD. Potential mechanisms for this role are examined. The use of serum TSA as a marker of atherosclerotic disease is evaluated.

The inborn errors of sialic acid metabolism and their laboratory investigation.

Sialic acid (SA), a terminal monosaccharide of glycoconjugates, has a central role in human biological function. Various point mutations result in the malmetabolism of SA and inherited disorders: Defective SA synthesis causes sialuria and defective SA catabolism causes sialidosis and sialic acid storage disease (SASD). These inborn errors of metabolism are characterised by increased urinary free SA. This article reviews biochemical and clinical features that are distinct to each disorder. In view of recent evidence indicating a wide underestimation in the prevalence of sialic acid disorders, laboratory methods for determining urinary free SA and its implications for screening and prenatal diagnosis are evaluated.

Efficacy of ezetimibe in patients with statin-resistant and statin-intolerant familial hyperlipidaemias.

OBJECTIVE: To investigate the efficacy of the cholesterol absorption inhibitor ezetimibe in patients with refractory familial hyperlipidaemia or intolerant to statin therapy. METHODS: This prospective study assessed the safety and efficacy of ezetimibe in 200 patients with refractory familial hyperlipidaemias not achieving a low-density-lipoprotein (LDL) cholesterol < 3 cholesterol < 3 mmol/L (116 mg/dL) including 22% intolerant to all statin therapy, many consuming intolerant to all statin therapy, many consuming sterol-containing products. RESULTS: Ezetimibe monotherapy resulted in 7% and 11% reductions in LDL-cholesterol and apolipoprotein B respectively. Ezetimibe-statin combination therapy reduced LDL-cholesterol by an additional 11 +/- 27% and apolipoprotein B by 11 (+79 to -18)%. There was a similar response between various sub-groups but a wide variation within groups with the greatest effect seen in patients groups with the greatest effect seen in patients under-responding to statins. The number of patients achieving the LDL-C target of 3 mmol/L rose from 5.5% to 18%. Non-significant effects included a 5 (+78 to -470)% reduction in triglycerides, 8 +/- 36% increment in HDL-cholesterol, 21 (+35 to -82)% reduction in C-reactive protein and a 1 (+20 to -50)% increase in alanine transaminase. No effects were seen on creatinine, creatine kinase, or insulin resistance. Fourteen patients (7%) discontinued ezetimibe: seven due to gastrointestinal side-effects, one patient developed an ezetimibe-induced hypercholesterolaemia (x 1.5), one developed ezetimibe-induced hypertriglyceridaemia (x 7) and five discontinued for other reasons. CONCLUSION: Ezetimibe is a useful addition to statins in patients with familial hyperlipidaemias but shows a highly variable response profile.

Impaired renal function and atherosclerosis in a Pakistani cohort.

OBJECTIVE: To investigate the relationship of creatinine and calculated glomerular filtration rate (GFR) with coronary arterial disease (CAD) in Pakistani patients. SUBJECTS: Four hundred individuals with chest pain; 200 with angiographic disease matched with 200 without occlusive disease. DESIGN: A prospective case-control study. SETTING: A tertiary referral cardiology unit in Pakistan. RESULTS: Impaired renal function as estimated by calculated GFR was common in this population. Creatinine and glomerular filtration rate, as calculated by the Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae, were associated with CAD and atherosclerotic burden in Pakistani patients. Calculation of creatinine clearance, correcting for age, sex and body mass index, showed that clearance was 81 (17-257) mL/min/1.73 m2 in patients with CAD compared with 88 (23-167) mL/min/1.73 m2 in controls with a significant number of patients (18.5 vs. 6.5%; RR = 2.85; p < 0.001) showing significant renal impairment (< 60 mL/min/1.73 m2) by CG and more by the MDRD equation (26 vs. 9%; RR = 2.88; p < 0.001). The unadjusted odds ratios for CAD for a GFR < 60 mL/min/1.73 m2 were 3.66 (1.87-7.16) and 3.29 (1.81-6.01), respectively and, after adjustment for diabetes, smoking, insulin resistance, inflammation and apolipoprotein A1, 1.04 (1.02-1.09) and 1.04 (1.02-1.09), respectively. CONCLUSIONS: Impaired renal function is common in Pakistani patients with coronary arterial disease and is strongly associated with a risk of atherosclerosis independent of insulin resistance.

Total sialic acid and associated elements of the metabolic syndrome in women with and without previous gestational diabetes.

OBJECTIVE: Inflammatory markers predict type 2 diabetes and relate to the metabolic syndrome. Gestational diabetes mellitus (GDM) predicts type 2 diabetes and may be part of this syndrome. To examine the association of inflammatory markers with GDM, we investigated total sialic acid (TSA) in women with and without previous GDM. RESEARCH DESIGN AND METHODS: All women with GDM and a random sample of women from one center of the Brazilian Study of Gestational Diabetes were invited to return 7 years after their index pregnancy. After an interview, an oral glucose tolerance test and anthropometry were performed. A total of 46 women with and 50 women without previous GDM completed the protocol. RESULTS: Mean TSA was significantly higher in women with (71.8 +/- 11.1 mg/dl) than without (67.5 +/- 9.8 mg/dl) previous GDM (P < 0.05). In a linear regression model, TSA was 4 mg/dl (P < 0.05) higher in women with previous GDM, after adjustment for BMI, fasting insulin sensitivity, and number of years spent in school. In a similar model, current 2-h plasma glucose levels were associated with higher TSA levels after adjustment for waist-to-hip ratio and the log of triglycerides. TSA was strongly correlated with individual components and aggregates (r = 0.55, P < 0.001) of the metabolic syndrome. CONCLUSIONS: Increased TSA levels are associated with previous GDM and are strongly linked to the metabolic syndrome. These findings in young women suggest that a chronic mild systemic inflammatory response is an early feature of the metabolic syndrome and that GDM may be a window for its investigation.

Use of lipid-lowering medications in myasthenia gravis: a case report and literature review.

We present a patient with myasthenia gravis (MG) who developed worsening of his condition after starting ezetimibe. We review the literature concerning lipid-modifying medications and MG. The use of bile acid sequestrant agents may have a place in the lipid management of MG patients because they did not seem to cause muscle-related side effects or worsening of MG.