Limitations of non-ceruloplasmin-bound copper in routine clinical practice.
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Ceruloplasmin↗
Biomedical subjects
A S Wierzbicki
Publications and source records attributed to A S Wierzbicki.
Statins and hypertension.
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Anticholesteremic Agents↗
Adjusting copper concentrations for caeruloplasmin levels in routine clinical practice.
BACKGROUND: An investigation on copper metabolism usually includes the measurement of serum levels of copper and caeruloplasmin. Using these levels, some laboratories derive levels of non-caeruloplasmin-bound copper (NCC); however, a considerable number of patients may show negative values, which is not physiologically possible. AIM: To derive an equation for adjusted copper in a manner similar to that widely accepted for adjusted calcium. METHODS: A linear regression equation for the relationship between caeruloplasmin and copper was used: [copper] (micromol/l) = 0.052x[caeruloplasmin] (mg/l). An equation for copper adjusted for caeruloplasmin was derived using this equation and the reference interval of 10-25 micromol/l for copper. RESULTS: The derived equation was [adjusted copper] (micromol/l) = [total copper] (micromol/l)+0.052x[caeruloplasmin] (mg/l)+17.5 (micromol/l). The adjusted copper concentrations on the 2.5th and 97.5th centiles were 12.7 and 21.5 micromol/l, respectively, with the population having a gaussian distribution. The relationship between NCC and the adjusted copper concentrations is linear and independent of caeruloplasmin concentration. CONCLUSION: Calculation of copper adjusted for caeruloplasmin uses the same variables as those for NCC. Accordingly, the problems that are caused by the lack of specificity of caeruloplasmin immunoassays are the same as those identified for NCC. This calculation, however, overcomes the negative values that are found in a considerable minority of patients with NCC, as well as age and sex differences in the caeruloplasmin reference interval. As the concept is already familiar to non-laboratory healthcare professionals in the form of calcium adjusted for albumin, this method is potentially less confusing than that for NCC.
Ceruloplasmin↗
FIELDS of dreams, fields of tears: a perspective on the fibrate trials.
Endpoint studies have been performed with fibrates in coronary heart disease since 1971. The results have been confusing - starting with initial benefits in small studies, but contradicted by either minimal benefits in the Coronary Drug Project or adverse noncardiovascular (non-CV) effects in the World Health Organization Clofibrate Study. Fibrates returned for patients with low HDL-C and low LDL-C after a 25% event reduction were seen in the Veterans Affairs HDL Intervention Trial. The greater prominence ascribed to the lipid triad of the metabolic syndrome and the increasing prevalence of diabetes increased the topicality of fibrates given their main action of converting small dense to light buoyant LDL. The Fenofibrate Intervention in Event Lowering in Diabetes (FIELD) Study has carried on the tradition. Fenofibrate therapy in 9795 patients comprising a mixed low-risk primary and a medium-risk secondary prevention cohort resulted in an 11% reduction in coronary events (p = 0.16), a similar but significant reduction in CV events (p = 0.04; number needed to treat = 70). The benefits were concentrated in primary prevention and on nonfatal myocardial events, but the study was confounded by asymmetrical statin drop-in due to the LDL-C-lowering effect of fenofibrate. Safety was generally good, including in combination with statins, but old concerns about sudden death, pancreatitis and venous thrombosis returned. Unexpected benefits were seen with fenofibrate on microvascular endpoints including microalbuminuria and retinopathy. Fenofibrate is a reasonable second-line therapy for dyslipidaemia in diabetes and safe in combination therapy. Its benefits on microvascular disease and in combination therapy require further confirmation.
Cardiovascular Diseases↗
Erectile dysfunction and statin treatment in high cardiovascular risk patients.
Erectile dysfunction (ED) has been associated with risk factors for atherosclerosis. Medications used for atherosclerosis have also been implicated in ED. The aim of this study is to investigate the relationship of erectile function to cardiovascular risk factors and specific drug therapies before and after 6 months of statin therapy. In this prospective observational study, International Index of Erectile Function (IIEF) scores were measured in 93 men attending cardiovascular risk clinics. Cardiovascular risk factors and drug therapies were assessed prior to initiation and after 6 months of statin therapy. Prior to statin therapy, the median IIEF score was 21 (range 0-25), and 57% had impairment of erectile function. After statin therapy, IIEF scores were reduced to 6.5 (range 0-25) (p < 0.001), and 22% experienced new onset ED. Before statin therapy no correlation was observed between IIEF score and any individual cardiovascular risk factor. After 6 months of statin therapy, correlations were observed between lower IIEF scores (r = 0.62; p < 0.001) and age and diabetes and weakly with smoking. Differences in dose, relative efficacy or relative lipophilicity of statin prescribed showed no correlation with change in IIEF score. This study suggests ED following statin therapy is more likely in patients with severe endothelial dysfunction due to established cardiovascular risk factors including age, smoking and diabetes.
Adult↗
Lipid lowering, statins and cancer.
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Humans↗
Rimonabant: endocannabinoid inhibition for the metabolic syndrome.
Rimonabant is the first drug to target the endocannabinoid (CB) pathway by inhibiting the actions of anandamide and 2-archidonyl-glycerol on CB1 receptors. This review gives an overview of rimonabant and the CB system and how this system relates to obesity. Rimonabant blocks the central effects of this neurotransmitter pathway involved in obesity and weight control and also blocks the direct effects of CBs on adipocyte and hepatocyte metabolism. Blockade of CB1 receptors leads to a decrease in appetite and also has direct actions in adipose tissue and the liver to improve glucose, fat and cholesterol metabolism so improving insulin resistance, triglycerides and high-density lipoprotein cholesterol (HDL-C) and in some patients, blood pressure. The Rimonabant in Obesity (RIO) trials have shown that rimonabant induces weight loss > 5% in 30-40% of patients and > 10% in 10-20% above both a dietary run-in and long-term hypocaloric management over a 2 year period with a low level of drug-related side effects. Rimonabant therapy is associated with an extra 8-10% increase in HDL-C and a 10-30% reduction in triglycerides and improvements in insulin resistance, glycaemic control in patients with diabetes and also adipokines and cytokines including C-reactive protein over hypocaloric diet therapy. In addition rimonabant abolishes the weight gain associated with smoking cessation and improves the chances of quitting smoking. Thus rimonabant has major effects on both the metabolic syndrome and cardiovascular risk factors thus has the potential to reduce the risks of type 2 diabetes and cardiovascular disease associated with the cardiometabolic phenotype.
Cannabinoid Receptor Modulators↗
Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection.
AIMS/HYPOTHESIS: Heterozygous mutations in the gene of the transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha) are considered a rare cause of MODY with only 14 mutations reported to date. The description of the phenotype is limited to single families. We investigated the genetics and phenotype of HNF-4alpha mutations in a large European Caucasian collection. METHODS: HNF-4alpha was sequenced in 48 MODY probands, selected for a phenotype of HNF-1alpha MODY but negative for HNF-1alpha mutations. Clinical characteristics and biochemistry were compared between 54 HNF-4alpha mutation carriers and 32 familial controls from ten newly detected or previously described families. RESULTS: Mutations in HNF-4alpha were found in 14/48 (29%) probands negative for HNF-1alpha mutations. The mutations found included seven novel mutations: S34X, D206Y, E276D, L332P, I314F, L332insCTG and IVS5nt+1G>A. I314F is the first reported de novo HNF-4alpha mutation. The average age of diagnosis was 22.9 years with frequent clinical evidence of sensitivity to sulphonylureas. Beta cell function, but not insulin sensitivity, was reduced in diabetic mutation carriers compared to control subjects (homeostasis model assessment of beta cell function 29% p<0.001 vs controls). HNF-4alpha mutations were associated with lower apolipoprotein A2 (p=0.001), A1 (p=0.04) and total HDL-cholesterol (p=0.02) than in control subjects. However, in contrast to some previous reports, levels of triglycerides and apolipoprotein C3 were normal. CONCLUSIONS/INTERPRETATION: HNF-4alpha mutations are common when no HNF-1alpha mutation is found in strictly defined MODY families. The HNF-4alpha clinical phenotype and beta cell dysfunction are similar to HNF-1alpha MODY and are associated with reduced apolipoprotein A2 levels. We suggest that sequencing of HNF-4alpha should be performed in patients with clinical characteristics of HNF-1alpha MODY in whom mutations in HNF-1alpha are not found.
Adolescent↗
Ezetimibe-induced hyperlipidaemia.
Ezetimibe is intestinally active cholesterol absorption inhibitor used to reduce low-density lipoprotein-cholesterol levels. This case report describes a novel side effect with this agent: ezetimibe-induced hyperlipidaemia in a patient with statin intolerance and familial combined hyperlipidaemia. Ezetimibe therapy induced an asymptomatic 770% increase in triglycerides (TGs) (3.51-27.1 mmol/l) and a 190% increase in total cholesterol (9.8-18.5 mmol/ 1) secondary to an increase (4.6-25.9 micromol/l; 560%) in hepatic cholesterol (lathosterol) synthesis. This lipid profile resolved 9 months after cessation of ezetimibe therapy. This report shows that ezetimibe may have long-lasting effects in man far exceeding its plasma half-life and that ezetimibe monotherapy can induce a large increase in hepatocyte very-low-density lipoprotein synthesis in rare individuals with a consequent mixed hyperlipidaemia or possibly hypercholesterolaemia depending on the metabolism and clearance of TG-rich lipoproteins.
Anticholesteremic Agents↗
Hypertriglyceridaemia and malignancy.
Severe hypertriglyceridaemia is a rare presentation usually associated with acute pancreatitis. We present two case reports of severe hypertriglyceridaemia occurring in patients with previous autoimmune disease and haematological and solid malignancies but no evidence of prior or concurrent pancreatitis or hyperlipidaemia. These case reports illustrate that haematological and solid organ malignancies and autoimmunity may be relevant as exacerbating factors in the presentation of severe type IV or V hypertriglyceridaemia.
Adult↗
Metabolic syndrome and risk of coronary heart disease in a Pakistani cohort.
OBJECTIVE: To assess the relation of the metabolic insulin resistance syndrome (M-IRS) with coronary heart disease (CHD) in Pakistani patients. SUBJECTS: 200 patients with angiographic disease (CHD(+)) matched with 200 patients with chest pain without occlusive disease (CHD(-)). DESIGN: Prospective case-control study. SETTING: Tertiary referral cardiology unit in Pakistan. RESULTS: M-IRS was present in 37% of CHD(+) versus 27% of CHD(-) patients by criteria for white patients or 47% versus 42%, respectively, by Asian criteria (p < 0.001). After adjustment for other risk factors, M-IRS was not a significant predictor for CHD or angiographic disease. Age (p = 0.03), smoking (p < 0.001), diabetes-years (p = 0.003), sialic acid (p = 0.01), and creatinine (p = 0.008) accounted for the excess risk of CHD. Similarly, age (p = 0.005), creatinine (p < 0.001), cigarette pack-years (p = 0.02), diabetes-years (p = 0.003), and sialic acid (p = 0.08) were predictors of greater angiographic disease. M-IRS differed between Pakistani and white patients, as waist circumference correlated weakly (r = -0.03-0.08, p = 0.45-0.52) with triglycerides, high density lipoprotein cholesterol, systolic blood pressure, or glucose. Sialic acid was the only inflammatory marker associated with M-IRS. CONCLUSIONS: Despite strong associations between individual risk factors associated with M-IRS and a univariate association between M-IRS and CHD in native Pakistanis, the principal discriminant risk factors in this group are age, smoking, inflammation, diabetes-years, and impaired renal function. The poor sensitivity of M-IRS for CHD reflects the high underlying prevalence of M-IRS, thus reducing sensitivity, confounding by other urban lifestyle traits, or a lack of association of waist circumference with M-IRS risk factors. The definition of M-IRS may have to be revised to increase its power as a discriminant risk factor for CHD in Pakistani populations.
Coronary Artery Disease↗
The use of ezetimibe in achieving low density lipoprotein lowering goals in clinical practice: position statement of a United Kingdom consensus panel.
There is no doubt that lowering serum cholesterol levels reduces the risk of major coronary events. This evidence has led treatment guidelines to set progressively lower targets for low density lipoprotein cholesterol (LDL-C). However, despite widespread use of statins, substantial numbers of patients do not achieve the LDL-C goals. Using higher doses of statins in an attempt to achieve these targets may increase the risk of serious adverse effects. Furthermore, the use of combination therapy with agents such as bile acid sequestrants, niacin and fibrates has been limited by increased potential for side effects, drug interactions and poor compliance. Ezetimibe, a selective cholesterol transport inhibitor, reduces the intestinal uptake of cholesterol without affecting absorption of triglycerides or fat-soluble vitamins. In clinical studies, ezetimibe 10 mg, in combination with statins or as monotherapy, was well tolerated and reduced LDL-C by 34-53% and 17-18%, respectively. The available evidence for ezetimibe is reviewed. The role of ezetimibe in increasing the proportion of patients attaining LDL-C treatment goals is discussed.
Anticholesteremic Agents↗
Effect of moxonidine on lipid subfractions in patients with hypertension.
Moxonidine is centrally acting imidazoline type-1 receptor agonist that significantly lowers blood pressure and has some insulin-sensitising actions. Its effects on plasma lipid profiles are uncertain. This study examined the effects of moxonidine on detailed lipid and lipoprotein profiles in 12 patients with hypertension and type 2b Fredricksen hyperlipidaemia. Treatment with moxonidine in six patients who completed the study resulted in a 10/5 mmHg reduction in 24-h ambulatory blood pressure (p = 0.01). A significant reduction in total and low-density-lipoprotein cholesterol (LDL-C) of 10% (p = 0.04) and 18% (p = 0.03), respectively, was seen. Triglycerides were reduced non-significantly by 23%, and high-density-lipoprotein cholesterol (HDL-C) was increased by 16%. There were no significant changes in apolipoprotein (apo) A-1 and B concentrations. No significant shifts were seen in HDL-C, LDL-C, very-low-density-lipoprotein cholesterol (VLDL-C) or apolipoprotein peak positions with therapy. Analysis of area under curve for each subfraction showed that moxonidine therapy resulted in a redistribution within the apoB profile. A slight non-significant reduction in VLDL apoB was seen. There was a reduction in the dense LDL apoB peak (p = 0.02) but less in the buoyant LDL apoB peak (p = 0.17) with a countervailing increase in LDL-C in the buoyant fraction (p = 0.01). The HDL-C and apoA-1 profile showed a shift from dense HDL apoA-1 (p = 0.01) to a buoyant HDL apoA-1sub-species (p = 0.01). These changes are consistent with a tendency for moxonidine to improve atherogenic lipid and lipoprotein profiles by actions on insulin-sensitisation and possibly through a direct cholesterol-reducing effect as seen with other imidazoles.
Antihypertensive Agents↗
Lipid-altering agents: the future.
Lipid-lowering is established as proven intervention to reduce atherosclerosis and its complications. This article summarises novel developments in the lipid-altering therapies under development. It also discusses other therapeutic targets, such as squalene synthase, microsomal transfer protein, acyl-cholesterol acyl transferase, cholesterol ester transfer protein, peroxosimal proliferator-activating receptors and lipoprotein (a), for which compounds have been developed and have at least reached trials in animal models. Lipid-altering drugs are likely to prove a fast-developing area for novel treatments, as possible synergies exist between new and established compounds for the treatment of atherosclerosis.
Arteriosclerosis↗
Does activity in research correlate with visibility?
BACKGROUND: A previous survey has highlighted the fact that most individuals in chemical pathology identifiable from specialist society membership failed to publish material in Medline cited journals during a five year period. It could be considered that published research that is not cited in other work is not useful unless it has achieved visibility, as demonstrated by citation in another research publication. AIMS: To determine whether the frequency of research publication is associated with research visibility. METHODS: A random selection from the previous survey was investigated to determine whether the frequency of research publication is associated with research visibility. RESULTS: There was a logarithmic relation between the frequency of publication and visibility, with an increasing probability of citation as publication frequency increases. CONCLUSIONS: If academic activity is to survive then individuals must stay active in research; this requires a continuing commitment to a tradition of support for individuals at all stages of their careers engaging in research.
Authorship↗
The casino of life.
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Clinical Laboratory Information Systems↗
Chemical pathology and the new contract for GPs.
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Contracts↗
Smell testing: an additional tool for identification of adult Refsum's disease.
BACKGROUND: Adult Refsum's disease (ARD) is characterised by the presence of retinitis pigmentosa, ataxia, deafness, sensory neuropathy, and bony changes. The diagnosis is confirmed by the presence of phytanic acidaemia. Although reduced smell function has been described in ARD, its value in the diagnosis of the condition has not been fully evaluated. OBJECTIVE: To investigate the prevalence and degree of olfactory dysfunction in patients with ARD. METHOD: The olfactory function of 16 patients with ARD was assessed using the quantitative University of Pennsylvania Smell Identification Test (UPSIT). RESULTS: All patients had complete anosmia or grossly impaired smell function with a mean UPSIT score of 14.7 (SD 4.7) (normal > 34) despite having been treated with an appropriate diet for a median of 15 years (range 1-25). CONCLUSIONS: Identification of ARD patients can be facilitated by using the UPSIT in combination with the presence of retinitis pigmentosa, even if they have no neurological or bony features. Phytanic acid screening should be performed in any patient manifesting these two signs.
Adolescent↗