Nonalcoholic fatty liver and metabolic syndrome in Italy: results from a multicentric study of the Italian Arteriosclerosis society.

Nonalcoholic fatty liver disease (NAFLD) is associated with all the components of metabolic syndrome (MS) and might to be considered an additional component of MS itself. The Italian Society for the Study of Atherosclerosis (SISA) in 2005 started a research project aimed to study the NAFLD, using ultrasound (US), in nondiabetic MS subjects matching at least one of the ATP III criteria for HDL-C or triglycerides [TG]. Prevalence of US-NAFLD and its associated risk factors and prevalence of hypertransaminasemia and its possible determinants were evaluated. NAFLD prevalence was 0.78. Men with steatosis compared to men without steatosis were younger (P < 0.05) with higher TG (P < 0.03), homeostasis model assessment insulin resistance (HOMA-R) (P < 0.003), and visceral fat thickness (VFT) (P < 0.0001). Women with steatosis showed higher TG (P < 0.05), HOMA-R (P < 0.04), VFT (P < 0.0001), and lower age (P < 0.05). At multivariate analyses, VFT (P < 0.0001), HOMA-R (P < 0.02), and TG/HDL (P < 0.05) were associated with severity of NAFLD. Age (P < 0.05), LogTG (P < 0.005), and VFT (P < 0.01) were associated with higher ALT. The US prevalence of steatosis in this study (0.78) is the highest reported in patients with MS. Considering the exclusion of severe obese and diabetic patients and the recruitment criteria, this finding highlights the prominent role played by the alterations of lipid metabolism in the pathogenesis of NAFLD.

Prediction of incident type 2 diabetes mellitus based on a twenty-year follow-up of the Ventimiglia heart study.

A novel algorithm to predict incident type 2 diabetes mellitus (iT2DM) is presented considering data from a 20-year prospective study in a Southern Italy population. Eight hundred and fifty-eight out of 1,351 subjects (24-85 years range of age) were selected. Incident type 2 diabetes was diagnosed in 103 patients in a 20-year follow-up. The Finnish Diabetes Risk Score (FINDRISC) and the Framingham Offspring Study simple clinical model (FOS) have been used as reference algorithms. Two custom algorithms have been created using Cox parametric hazard models followed by PROBIT analyses: the first one (VHSRISK) includes all the study subjects and the second one (VHS95RISK) evaluates separately subjects with baseline fasting blood glucose (FBG) above/below 5.2 mmol/L (95 mg/dL). The 44 iT2DM cases below 5.2 mmol/L of baseline FBG were predicted by high LDL cholesterol, metabolic syndrome (ATPIII criteria), BMI > 30 kg/m(2), and high factor VII activity. The 59 cases above the FBG threshold were predicted by FBG classes, hypertension, and age. ROC areas for iT2DM prediction were: FINDRISC = 0.759, FOS = 0.762, VHSRISK = 0.789, and VHS95RISK = 0.803. In a Mediterranean population, the use of a custom generated algorithm evaluating separately low/high FBG subjects improves the prediction of iT2DM in subjects classified at lower risk by common estimation algorithms.

Non-pharmacological control of plasma cholesterol levels.

The importance of non-pharmacological control of plasma cholesterol levels in the population is increasing, along with the number of subjects whose plasma lipid levels are non-optimal, or frankly elevated, according to international guidelines. In this context, a panel of experts, organized and coordinated by the Nutrition Foundation of Italy, has evaluated the nutritional and lifestyle interventions to be adopted in the control of plasma cholesterol levels (and specifically of LDL cholesterol levels). This Consensus document summarizes the view of the panel on this topic, with the aim to provide an updated support to clinicians and other health professionals involved in cardiovascular prevention.

The metabolic syndrome predicts cardiovascular events in subjects with normal fasting glucose: results of a 15 years follow-up in a Mediterranean population.

UNLABELLED: The aim of this study was to evaluate the cardiovascular (CV) risk due to the metabolic syndrome in a 15-year prospective study of a Sicilian population. In the Mediterranean area obesity is highly prevalent, but epidemiological data on the metabolic syndrome are limited. METHODS AND RESULTS: Among the 1351 subjects enrolled in the "Ventimiglia di Sicilia" epidemiological project, we selected 687 subjects between 35 and 75 years of age; baseline parameters were assessed and subjects have been followed for 15 years recording CV events, total and cardiovascular mortality. The metabolic syndrome was defined according to both the Adult Treatment Panel III and the International Diabetes Federation criteria. Metabolic syndrome (ATPIII criteria) was significantly (p<0.00001) more prevalent in women (31.5%) than in men (12.4%). The metabolic syndrome increased the risk of CV events with a hazard ratio of 1.9 (confidence interval CI; 1.46-2.46). Using a Cox proportional hazards estimation model, the survival curve of subjects with metabolic syndrome and normal fasting glucose did not significantly differ from the curve of subjects with metabolic syndrome and impaired fasting glucose (IFG). CONCLUSIONS: In a 15-year follow-up the metabolic syndrome is predictive of CV events regardless of the presence of IFG or diabetes mellitus.

Interleukin 6 plasma levels predict with high sensitivity and specificity coronary stenosis detected by coronary angiography.

In recent years new biomarkers able to measure the coronary atherosclerotic burden have been investigated. The aim of the present study was: i) to measure plasma levels of four biomarkers: C reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin 6 (IL-6), 8-isosprostane (8-ISO), in a series of patients undergoing coronary angiography; ii) to assess the power of the biomarkers to predict critical coronary stenosis detected by angiography. The study population consisted of a group of 438 subjects undergoing coronary angiography; 160 patients with 0, 1, 2, or 3 critical vessels were selected, and biomarkers plasma levels were measured in plasma samples obtained before the procedure. The most predictive biomarker was then assayed in 120 patients with critical stenosis and 120 unmatched patients without stenosis. CRP, sICAM-1, IL-6 and 8-ISO plasma levels increased with the number of diseased vessels. All biomarkers were good predictors of critical stenosis (receiver-operator-curve [ROC] areas; CRP = 0.880, IL-6 = 0.936, sICAM-1 = 0.907, 8-ISO = 0.873). IL-6 was confirmed in an expanded sample of 240 subjects to be the best predictor with a ROC area = 0.959. With a threshold of 3.6 ng/l, a 100% sensitivity (120/120) and a 90% specificity (108/120) was observed. In conclusion, IL-6, sICAM-1, CRP and 8-ISO are predictive of CAD. IL-6 predicts critical coronary stenosis with the highest sensitivity and specificity.

Low-density lipoproteins generated during an oral fat load in mild hypertriglyceridemic and healthy subjects are smaller, denser, and have an increased low-density lipoprotein receptor binding affinity.

Triglyceride-rich lipoproteins generated during the postprandial phase are atherogenic. Large very low-density lipoproteins (LDLs) or chylomicrons (CMs) are not as atherogenic as their remnants (Rem). Small and dense LDLs are associated with cardiovascular disease. Low-density lipoprotein size is partly under genetic control and is considered as a relatively stable LDL feature. In this article, we present data on retinyl palmitate kinetics correlated with the modification of LDL features in terms of size, density, and in vitro receptor binding affinity after an oral fat load. Six nondiabetic, hypertriglyceridemic (HTG) patients and 6 healthy controls were examined. Low-density lipoprotein size was assessed by gradient gel electrophoresis, and LDL density by density gradient ultracentrifugation. Low-density lipoprotein binding affinity was tested by in vitro competition binding assay on normal human skin fibroblasts (HSFs) and hepatoma cells (HepG2). Kinetic parameters were estimated in CM and Rem fractions by compartmental modeling. Hypertriglyceridemic patients showed significantly higher triglyceride area and a slower CM fractional catabolic rate. Postprandial LDL density increased both in HTG patients and in the control group with a significant difference between groups at 6 hours. Fasting LDL size was lower in HTG patients vs controls but decreased similarly in the postprandial phase. Low-density lipoprotein size and density postprandial modifications were not correlated with any investigated parameter. Postprandial LDLs were internalized more efficiently by HSF than baseline LDL only in the HTG group. In conclusion, postprandial LDLs are smaller and denser compared with fasting LDLs after an oral fat load. Postprandial LDLs also slightly increased their affinity to the HSF cell receptors.

Accumulation of apoE-enriched triglyceride-rich lipoproteins in patients with coronary artery disease.

Triglycerides (TGs) are vehicled by multiple particles with different abilities to promote atherosclerosis. Among plasma TG-rich lipoproteins (TRLs), subspecies may or may not contain apolipoprotein E (apoE) molecules: in this study, we evaluated the relative contribution of apoE-rich and apoE-poor TRLs to coronary atherosclerosis. We selected a group of males with premature coronary artery disease (CAD) without any of the classical nonlipid risk factors and/or high plasma lipid levels and evaluated the plasma concentration of TRL subspecies in comparison with healthy controls. Patients with CAD and controls had total cholesterol and TG levels within the normal range (despite slightly, even if significantly, higher TG levels in patients with CAD) and low-density lipoprotein cholesterol levels near optimal values. Nevertheless, patients with CAD had significantly lower high-density lipoprotein cholesterol, smaller low-density lipoprotein peak particle size, and a reduced HDL2b subfraction than controls. In addition, we observed higher concentrations of total TRL in patients with CAD together with a selective increase in apoE-rich particles. All these data were confirmed after correction for TG levels. We also investigated which parameters were associated with the spread of coronary atherosclerosis. Subjects with a single-vessel disease had selectively lower levels of apoE-rich fractions than patients with a multivessel disease. This was confirmed by multivariate analysis. Patients with a premature CAD free of nonlipid conventional risk factors, despite not having elevated lipid levels, show several lipoprotein abnormalities. Besides known atherogenic alterations, the accumulation of apoE-rich TRL subfractions may represent an additive factor that can potentially promote and initiate the atherosclerotic process.

Six novel mutations of the LDL receptor gene in FH kindred of Sicilian and Paraguayan descent.

Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease caused by mutations in the gene coding for the low density lipoprotein receptor (LDL-R). It is characterized by a high concentration of low density lipoprotein (LDL), which frequently gives rise to premature coronary artery disease. We studied the probands of five FH Sicilian families with 'definite' FH and one proband of Paraguayan descent with homozygous FH who has been treated with an effective living-donor liver transplantation. In order to seek the molecular defect in these six families, we used direct sequencing to define the molecular defects of the LDL-R gene responsible for the disease. We described three novel missense mutations (C100Y, C183Y and G440C), two frameshift mutations (g.1162delC in exon 8 and g.2051delC in exon 14) and one mutation (g.2390-1Gright curved arrow A) at splicing acceptor consensus sequences located in intron 16 of the LDL-R gene; the analysis of cDNA of this splicing mutation showed the activation of a cryptic splice site in intron 16 and the binding studies showed a reduction in internalisation of LDL-DIL in the proband's cultured fibroblasts. Moreover, a g.2051delC in exon 14 was identified in the proband of Paraguayan ancestry with clinical features of homozygous FH. The mutation identified in the South American patient represents the first description of a variant in South American patients other than Brazilian FH patients. The 5 mutations identified in the Sicilian patients confirm the heterogeneity of LDL-R gene mutations in Sicily.

Riskard 2005. New tools for prediction of cardiovascular disease risk derived from Italian population studies.

BACKGROUND AND AIM: The need to update tools for the estimate of cardiovascular risk prompted the "Gruppo di Ricerca per la Stima del Rischio Cardiovascolare in Italia" to produce a new chart and new software called Riskard 2005. METHODS AND RESULTS: Data from 9 population studies in 8 Italian regions, for a grand total of 17,153 subjects (12,045 men and 5,108 women) aged 35-74 and for a total exposure of about 194,000 person/years were available. A chart for the estimate of cardiovascular risk (major coronary, cerebrovascular and peripheral artery disease events) in 10 years was produced for men and women aged 45-74 free from cardiovascular diseases. Risk factors employed in the estimate were sex, age (6 classes), systolic blood pressure (4 classes), serum cholesterol (5 classes), diabetes, and cigarette smoking (4 classes). Estimates were produced for absolute risk and for relative risk, the latter against levels expected in the general population that produced the risk functions. Software was produced for the separate estimate of major coronary, cerebrovascular and cardiovascular events (the latter made by coronary, cerebrovascular and peripheral artery disease of atherosclerotic origin) for follow-up at 5, 10 or 15 years, in men a women aged 35-74 years at entry and free from cardiovascular diseases. Risk factors employed here were sex, age, body mass index, mean physiological blood pressure, HDL cholesterol, non-HDL cholesterol, cigarette smoking, diabetes and heart rate. The output is based on several indicators: absolute risk, relative risk (as defined above), ideal risk (for a very favourable risk profile), biological age of risk, comparisons among the above indicators, the percent contribution of risk factors to the excess of estimated risk above the level of the ideal risk, and the description of trends in risk estimate in relation to repeated measurements. CONCLUSIONS: These tools represent progress compared to similar tools produced some years ago by the same Research Group.

Family history, diabetes and extension of coronary atherosclerosis are strong predictors of adverse events after PTCA: A one-year follow-up study.

BACKGROUND AND AIM: In this study we addressed some open questions in patients with coronary artery disease (CAD). First, we analysed which of the traditional risk factors was associated with the spreading of coronary stenosis and second, we aimed to identify if any variable was predictive of post-percutaneous transluminal coronary angioplasty (PTCA) clinical events. METHODS AND RESULTS: We collected a consecutive series of patients with CAD (n=301) and in the subgroup of patients undergoing PTCA (n=135) we performed a prospective one-year follow-up study recording cardiovascular morbidity and total mortality. According to the extension of coronary atherosclerosis, we found a significant relationship with the prevalence of diabetes in men and with plasma HDL-cholesterol concentrations in women. The follow-up was completed in 95% of patients; we did not document any death whereas clinical events were registered in 16% of patients. At univariate analysis, we found that patients with clinical events had a higher prevalence of family history of CAD (43% vs 14%, p<0.005), diabetes (52% vs 21%, p<0.005) and multivessel disease (52% vs 35%, p<0.05). Multivariate analysis (logistic regression) confirmed that family history of CAD (OR 4.6, 95% CI 1.7-12.8, p<0.005), diabetes (OR 4.0, 95% CI 1.5-10.6, p<0.01) and multivessel disease (OR 2.8, 95% CI 1.1-7.4, p<0.05) were the only variables predictive of clinical events. CONCLUSIONS: In this study, factors associated with the spreading of coronary stenosis were different according to the gender. Moreover, the presence of diabetes and multivessel disease had a negative impact on the long-term prognosis of patients undergoing PTCA. In addition, the family history of CAD represented in our study a strong predictor of clinical events. We suggest that in the management of post-PTCA patients, the role of individual baseline clinical characteristics must be taken into account and that subjects with a family history of premature CAD, diabetes and a wide extension of coronary disease represent those with the highest risk.

Cystatin C levels are decreased in acute myocardial infarction: effect of cystatin C G73A gene polymorphism on plasma levels.

BACKGROUND: Cystatin C is the most abundant protease inhibitor in the plasma. Low plasma levels have been found in patients with aortic aneurysms and they seem correlated with the extension of the aortic lesions in early aneurysms detected by ultrasonography. METHODS: In this study, plasma levels of cystatin C have been investigated in patients with acute myocardial infarction (AMI), unstable angina and controls. The effect on plasma levels of the G73A polymorphism of the CST3 gene has been also evaluated. RESULTS: Patients with acute myocardial infarction showed significantly lower levels of cystatin C compared to unstable angina and controls, but levels were nearly normal in a week after the acute event. The genotype distribution of the G73A polymorphism was not different among the groups. Nevertheless, cystatin C levels decreased proportionally with the number of A alleles. Cystatin C levels were positively correlated with age, triglyceride/HDL cholesterol ratio and creatinine, and negatively with HDL cholesterol and the number of A alleles. All variables, but not HDL cholesterol, were independently correlated in a multivariate analysis. CONCLUSIONS: Cystatin C is decreased in acute myocardial infarction. It is still not clear whether lower cystatin C levels are causally linked to the acute event or just represent a negative acute phase response. The CST3 gene G73A polymorphism functionally affects cystatin C plasma levels.

A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke.

CONTEXT: Myocardial infarction (MI) and ischemic stroke are thought to be caused by matrix digestion by metalloproteinases (MMPs) leading to rupture of atherosclerotic plaques. Production of macrophage MMP-2 and MMP-9 is induced by cyclooxygenase 2 (COX-2) and prostaglandin E(2) synthesis. Although COX-2 expression may be genetically determined, the relation between COX-2 polymorphisms and the risk of MI and stroke is unclear. OBJECTIVE: To investigate the relationship between the -765G-->C polymorphism of the COX-2 gene and clinically evident plaque rupture. DESIGN, SETTING, AND PARTICIPANTS: Prospective, matched case-control study conducted between March 2002 and October 2003 among 864 patients with first MI or atherothrombotic ischemic stroke and 864 hospitalized controls. The groups were matched for age, sex, body mass index, smoking, hypertension, hypercholesterolemia, and diabetes. The -765G-->C variant of the COX-2 gene was genotyped by restriction endonuclease digestion of polymerase chain reaction products. MAIN OUTCOME MEASURES: Presence of the -765G-->C polymorphism of the COX-2 gene; COX-2, MMP-2, and MMP-9 expression and activity in plaques and in peripheral monocytes; urinary 6-keto PGF1alpha (marker of endothelial prostacyclin); and endothelium-dependent and -independent forearm blood flow vasodilation. RESULTS: The prevalence of -765GC was 2.41 times higher among controls than among cases (43.3% vs 17.9%; P<.001). The prevalence of -765CC homozygosity was 5.81 times higher (6.4% vs 1.1%; P =.04). Among participants carrying the -765GC and -765CC genotypes, the prevalence ratios for MI or stroke were 0.48 (95% CI, 0.36-0.68) and 0.33 (95% CI, 0.24-0.55), respectively. Expression of COX-2 and MMPs was significantly lower in atherosclerotic plaques from participants carrying the -765C allele, while the -765G-->C polymorphism did not affect endothelial prostacyclin biosynthesis or endothelium-dependent vasodilation in vivo. In subgroup analyses (n = 224 cases), serum high-sensitivity C-reactive protein was significantly lower in patients carrying the -765C allele (mean [SD], 0.78 [0.1] vs 2.56 [0.4] mg/L; P =.04). CONCLUSIONS: We found that the -765G-->C polymorphism of the COX-2 gene is associated with a decreased risk of MI and stroke. Detection of this genotype may be useful for predicting genetic risk of MI and stroke.

Beta-2-glycoprotein I is growth regulated and plays a role as survival factor for hepatocytes.

Beta-2-glycoprotein I (beta(2)GPI) is mainly produced by the liver and is found in plasma partially associated to lipoproteins. Although various properties have been attributed to this protein, its physiological role remains still unclear. We investigated its expression in cultured liver cells and in regenerating liver. Expression studies in HepG2 cells demonstrate that beta(2)GPI mRNA is regulated in a cell cycle-dependent manner, with very low expression in low cycling conditions and increasing levels in proliferating cells. p21 WAF-dependent growth arrest, induced by butyrate treatment, down-regulate beta(2)GPI mRNA levels. Immunolocalization in normal rat liver shows a non-homogeneous pattern, being mainly present in the centrolobular area; post-hepatectomy regenerating rat liver is uniformly immunostained and mitotic elements show the highest protein expression. Albumin gene expression, studies as control liver specific product, was not affected by sodium butyrate induced growth arrest. As previously reported for endothelial cells, beta(2)GPI behaves as survival factor for HepG2 cells: when increasing amounts of the protein (10-50 microg) have been added to serum deficient cultured liver cells a progressive reduced cell loss was observed. In conclusion, the present data demonstrate that beta(2)GPI gene expression is strictly related to the proliferative status of hepatic cells and that this protein could play a role in maintaining liver cells vitality when exposed to different stress factors such as regeneration after partial hepatectomy or growth factors depletion.

Screening for celiac disease in non-Hodgkin's lymphoma patients: a serum anti-transglutaminase-based approach.

Several studies have shown the existence of an association between celiac disease (CD) and non-Hodgkin's lymphoma (NHL). Our aim was to evaluate the usefulness of the serum anti-tissue transglutaminase (anti-tTG) antibody assay in screening for CD in consecutive NHL patients. In all, 80 consecutive patients (median age 61 years) with a new diagnosis of NHL were included. To compare the frequency of CD and of positive results for the anti-tTG assay, we enrolled 500 blood donors. In all patients serum anti-tTG was determined with two different ELISA: one based on tTG from guinea pig (gp-tTG) and the other based on human recombinant t-TG (h-tTG) as the antigens. Serum anti-endomysial antibodies (EmA) were also assayed. Subjects with positive serum EmA and/or anti-tTG underwent intestinal biopsy for histology study, HLA-DQ phenotype determination, and serum anti-gliadin (AGA) assay. Eight of 80 (10%) NHL patients were positive for anti-tTG ELISA--two of these exclusively for anti-gp-tTG and six for anti-h-tTG (7.5%). None of the 80 NHL patients were positive for serum EmA. The frequency of anti-tTG positivity in the blood donor controls was 2/500 (0.4%), significantly lower than that observed in the NHL patients (P < 0.0001). Both these blood donors were found to have CD. Only in one anti-h-tTG-positive NHL patient was there intestinal mucosa atrophy, and follow-up confirmed a CD diagnosis (CD frequency in NHL patients is 1.2%; versus blood donors: P = 0.4). In all the other seven anti-tTG-positive NHL patients a normal intestinal architecture was found, although, inflammatory infiltration of the lamina propria was observed in four patients. No anti-tTG-positive NHL patients, including the subject diagnosed as having CD, had a family history of CD, and all had normal weight and no signs of malabsorption. Anti-tTG false positive results were associated with a higher frequency of serum autoantibody positivity and T-cell type NHL. In conclusion, NHL patients the anti-tTG assay often gives discordant data with the EmA assay, with a high frequency of anti-tTG false positive results for CD diagnosis.

Autoimmune enteropathy and colitis in an adult patient.

The presence of circulating autoantibodies to gut enterocytes has been very rarely described in adults and is considered a possible cause of refractory sprue. Our aims was to describe the case of an adult patient with serum anti-enterocyte autoantibodies associated with a clinical picture characterized by involvement of both the small intestine and colon. A female, age 50, had suffered from diarrhea with mucus and blood, abdominal pain, thinness, anemia, and leukopenia since the age of 20. She also suffered from HCV infection and had mild chronic hepatitis. Family history was positive for autoimmunity. Symptoms were reported to worsen after eating gluten-containing foods, but anti-transglutaminase and anti-endomysial antibodies were negative. Intestinal histology showed mild, patch villous atrophy with a high intraepithelial lymphocyte count, but a normal number of intraepithelial lymphocytes carrying the gamma/delta+ receptor. HLA was: A11, A31 (19), B52 (5), DR 15 (2), DR 14 (6), DR 51, DR 52, DQ1. Colonoscopy did not show ulcerations or erosions and colon histology showed a moderate inflammatory infiltrate without minor crypt distortion or granuloma. RAST tests were positive for lactalbumin, lactoglobulin, casein, egg, and gliadin. After commencement of an oligoantigenic diet, stool frequency initially decreased, but the presence of mucus in the stools persisted, with episodes of bloody diarrhea. After one year of diet, nutritional parameters were low and anemia associated with a low leukocyte count persisted. Upper and lower gastrointestinal endoscopy and histology of the small intestine and colon were virtually unchanged. Consequently, natural autoantibodies and enterocyte autoantibodies were assayed. The patient was positive for IgG class enterocyte autoantibodies at a titer of 1:34. No other organ-specific or non-organ-specific autoantibodies were positive. Prednisolone treatment was started and the symptoms improved. After one year of this treatment plus elimination diet she was reevaluated. Bowel movement frequency was normal, body weight increased, and the asthenia had completely regressed. IgG anti-enterocyte autoantibodies were absent. Histology of the distal duodenum showed a normal villus/crypt ratio and IEL infiltration was reduced. Colon histology showed a reduction in inflammatory infiltrate in the lamina propria. In conclusion, we report a case of generalized gut disorder in an adult patient, affecting both the small intestine and the colon and characterized by the presence of circulating anti-enterocyte autoantibodies. Systematic testing for enterocyte autoantibodies should be performed not only in patients with refractory sprue, but also in subjects with upper and lower intestinal symptoms who have not been definitively diagnosed.

Diagnostic accuracy of fecal calprotectin assay in distinguishing organic causes of chronic diarrhea from irritable bowel syndrome: a prospective study in adults and children.

BACKGROUND: Fecal calprotectin (FC) has been proposed as a marker of inflammatory bowel disease (IBD), but few studies have evaluated its usefulness in patients with chronic diarrhea of various causes. We evaluated the diagnostic accuracy of a FC assay in identifying "organic" causes of chronic diarrhea in consecutive adults and children. METHODS: We consecutively enrolled 70 adult patients (30 males, 40 females; median age, 35 years) and 50 children (20 males, 30 females; median age, 3.5 years) with chronic diarrhea of unknown origin. All patients underwent a complete work-up to identify the causes of chronic diarrhea. FC was measured by ELISA. RESULTS: In adult patients, FC showed 64% sensitivity and 80% specificity with 70% positive and 74% negative predictive values for organic causes. False-positive results (8 of 40 cases) were associated with the use of aspirin (3 cases) or nonsteroidal antiinflammatory drugs (1 case) and with the presence of concomitant liver cirrhosis (3 cases). False-negative results mainly included patients suffering from celiac disease (5 cases). Patients with IBD (9 cases) were identified with 100% sensitivity and 95% specificity. In pediatric patients, sensitivity was 70%, specificity was 93%, and positive and negative predictive values were 96% and 56%. False-negative results (11 of 35 cases) were associated mainly with celiac disease (6 cases) or intestinal giardiasis (2 cases). CONCLUSIONS: FC assay is an accurate marker of IBD in both children and adult patients. In adults, false negatives occur (e.g., in celiac disease) and false-positive results are seen in cirrhosis or users of nonsteroidal antiinflammatory drugs. Diagnostic accuracy is higher in children.

Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial.

BACKGROUND: Despite the established efficacy of statins, many patients do not achieve recommended LDL cholesterol (LDL-C) goals. Contributing factors may be inadequate dosing, increased risk for adverse effects with high-dose monotherapy, and increased potential for intolerance and adverse effects with combinations of available agents. METHODS AND RESULTS: In a double-blind study, 628 patients with baseline LDL-C 145 to 250 mg/dL and triglycerides < or =350 mg/dL were randomly assigned to receive 1 of the following for 12 weeks: ezetimibe (10 mg/d); atorvastatin (10, 20, 40, or 80 mg/d); ezetimibe (10 mg) plus atorvastatin (10, 20, 40, or 80 mg/d); or placebo. The primary efficacy end point was percentage reduction in LDL-C for pooled ezetimibe plus atorvastatin versus pooled atorvastatin treatment groups. Ezetimibe plus atorvastatin significantly improved LDL-C, HDL cholesterol (HDL-C), triglycerides, total cholesterol:HDL-C, and high-sensitivity C-reactive protein (hs-CRP) compared with atorvastatin alone (P<0.01). Coadministration of ezetimibe provided a significant additional 12% LDL-C reduction, 3% HDL-C increase, 8% triglyceride reduction, and 10% hs-CRP reduction versus atorvastatin alone. Ezetimibe plus atorvastatin provided LDL-C reductions of 50% to 60%, triglyceride reductions of 30% to 40%, and HDL-C increases of 5% to 9%, depending on atorvastatin dose. LDL-C reductions with ezetimibe plus 10 mg atorvastatin (50%) and 80 mg atorvastatin alone (51%) were similar. CONCLUSIONS: Ezetimibe plus atorvastatin was well tolerated, with a safety profile similar to atorvastatin alone and to placebo. When coadministered with atorvastatin, ezetimibe provided significant incremental reductions in LDL-C and triglycerides and increases in HDL-C. Coadministration of ezetimibe and atorvastatin offers a well-tolerated and highly efficacious new treatment option for patients with hypercholesterolemia.

Differential apolipoprotein(a) isoform expression in heterozygosity is an independent contributor to lipoprotein(a) levels variability.

BACKGROUND AND METHODS: Lipoprotein(a) [Lp(a)] levels represent an independent risk factor for cardio- and cerebrovascular diseases. Since lipoprotein(a) levels show a wide variability even in subjects with similar apolipoprotein(a) isoforms, we investigated the contribution of apolipoprotein(a) heterozygosity to lipoprotein(a) variance. Lipoprotein(a) levels, apolipoprotein(a) isoforms identification and expression, and the correlation with other lipo-apolipoprotein parameters have been investigated in 628 subjects >18 years of age. RESULTS: In our study, 246 subjects were found heterozygous for apolipoprotein(a) isoforms. Lipoprotein(a) levels were higher in females. About 40% of the subjects expressed the larger isoform more intensely than the dominant isoform. Lipoprotein(a) was correlated with apolipoprotein(a) dominant isoform size, HDL-cholesterol and smaller apolipoprotein(a) isoform expression rate. Lipoprotein(a) was independently correlated with the smaller apolipoprotein(a) isoform, with its expression rate and with LDL-cholesterol. The inclusion of the smaller apolipoprotein(a) expression rate in a multiple regression model explained at least an additional 4% of the lipoprotein(a) variance after correction for apolipoprotein(a) size. CONCLUSIONS: The smaller isoforms are not always effectively dominant in heterozygosis since 40% of the subjects expressed more the larger isoform. The individual variability of apolipoprotein(a) isoform expression in heterozygosis could explain part of the lipoprotein(a) levels variability.