Roger K. Schindhelm

Alanine aminotransferase as a marker of non-alcoholic fatty liver disease in relation to type 2 diabetes mellitus and cardiovascular disease.

For a long time, hepatic steatosis was believed to be a benign condition. Only recently, liver steatosis, also termed non‐alcoholic fatty liver disease (NAFLD), has gained much interest. In most cases of NAFLD, a condition regarded as the hepatic component of the metabolic syndrome, the enzyme alanine aminotransferase (ALT) is elevated and consequently has been used as a marker for NAFLD. More recently, several cross‐sectional and prospective studies have demonstrated associations of this liver enzyme with features of the metabolic syndrome and type 2 diabetes mellitus. This review discusses the biochemical and metabolic properties of ALT, its applicability as a marker of NAFLD and describes its possible role in the pathogenesis of the metabolic syndrome and type 2 diabetes mellitus and subsequent cardiovascular disease. In addition, treatment strategies to ameliorate NAFLD and the associated risks are discussed. Copyright

Myeloperoxidase: a useful biomarker for cardiovascular disease risk stratification?

BACKGROUND Inflammation and oxidative stress are associated with atherosclerosis. Myeloperoxidase (MPO) is linked to both inflammation and oxidative stress by its location in leukocytes and its role in catalyzing the formation of oxidizing agents. Recent evidence suggests that MPO activity precipitates atherogenesis. Measurement of MPO in plasma may therefore contribute to cardiovascular disease (CVD) risk stratification. CONTENT Cross-sectional studies, case-control studies, and prospective-cohort studies investigating the relation between MPO and CVD have been evaluated. Differences in study populations, sample materials, sample handling, and assays were ascertained. Potential causal mechanisms linking MPO to accelerated atherosclerosis are discussed here. A majority of studies indicate that measurement of MPO in plasma was associated with improved CVD risk stratification above and beyond risk stratification results obtained with markers used in routine clinical practice. However, comparison of these epidemiological studies with regard to MPO and outcome is hampered because the reported MPO concentration depends on the assay method, sampling material, and preanalytical and analytical procedures. The link between MPO and CVD can, at least partly, be explained by MPO-dependent oxidation of LDL and HDL, subsequently leading to cholesterol accumulation in the arterial wall. Furthermore, MPO may reduce the bioavailability of nitric oxide, resulting in endothelial dysfunction. Finally, MPO destabilizes atherosclerotic plaques. SUMMARY Increasing evidence suggests that MPO is causally linked to atherosclerosis and its measurement may improve CVD risk estimation. Before MPO can be used in routine clinical practice, however, standardization of sampling and laboratory procedures is needed.

Alanine aminotransferase and the 6-year risk of the metabolic syndrome in Caucasian men and women: the Hoorn Study

Aims  To study the association between alanine aminotransferase (ALT) and the 6‐year risk of the metabolic syndrome in a population‐based study in Caucasian men and women.

Overweight is highly prevalent in children with type 1 diabetes and associates with cardiometabolic risk.

OBJECTIVES To determine the prevalence of traditional cardiometabolic risk factors and to assess the effect of overweight/obesity on the occurrence of these risk factors in a cohort of children with type 1 diabetes mellitus (T1DM). STUDY DESIGN Two hundred eighty-three consecutive patients (3 to 18 years of age) attending an outpatient clinic for T1DM care were included. The prevalence of cardiometabolic risk factors, the metabolic syndrome, and high alanine aminotransferase, were assessed before and after stratification for weight status. RESULTS Of all children (median age, 12.8 years; interquartile range, 9.9 to 16.0; median diabetes duration, 5.3 years; interquartile range, 2.9 to 8.6), 38.5% were overweight/obese (Z-body mass index > or =1.1). Overall, median HbA1c levels were 8.2% (interquartile range, 7.4 to 9.8), and HbA1c > or =7.5% was present in 73.9%. Microalbuminuria was found in 17.7%, high triglycerides (>1.7 mmol/L) in 17.3%, high LDL-cholesterol (>2.6 mmol/L) in 28.6%, low HDL-cholesterol (<1.1 mmol/L) in 21.2%, and hypertension in 13.1% of patients. In the overweight/obese children with T1DM, versus normal-weight children, a higher prevalence of hypertension (23.9% vs 5.7%), the metabolic syndrome (25.7% vs 6.3%), and alanine aminotransferase >30 IU/L (15.6% vs 4.5%) was found (all P < .05). CONCLUSIONS Overweight/obesity and cardiometabolic risk factors were highly prevalent in a pediatric cohort with T1DM. Hypertension, the metabolic syndrome, and high alanine aminotransferase were significantly more prevalent in overweight/obese compared with normal-weight children with T1DM.

Ethnic differences in cardiometabolic risk profile in an overweight/obese paediatric cohort in the Netherlands: a cross-sectional study

BackgroundDifferences in prevalence of cardiometabolic risk factors between different ethnic groups are largely unknown. We determined the variation in cardiometabolic risk profile according to ethnicity in a cohort overweight/obese Dutch children.MethodsAn oral glucose tolerance test was performed in 516 overweight/obese Dutch children of multi-ethnic origin, attending an obesity out-patient clinic of an urban general hospital (mean age 10.6 ± 3.2; 55.2% boys). Anthropometric parameters and blood samples were collected, and the prevalence of (components of) the metabolic syndrome (MetS) and insulin resistance were determined in each ethnic group.ResultsMajor ethnic groups were Dutch native (18.4%), Turkish (28.1%), and Moroccan (25.8%). The remaining group (27.7%) consisted of children with other ethnicities. Turkish children had the highest mean standardized BMI compared to Dutch native children (P < 0.05). As compared to Moroccan children, they had a higher prevalence of MetS (22.8% vs. 12.8%), low HDL-cholesterol (37.9% vs. 25.8%), hypertension (29.7% vs. 18.0%) and insulin resistance (54.9% vs. 37.4%, all P < 0.05). Although Turkish children also had higher prevalences of forementioned risk factors than Dutch native children, these differences were not statistically significant. Insulin resistance was associated with MetS in the Turkish and Moroccan subgroup (OR 6.6; 95%CI, 2.4–18.3 and OR 7.0; 95%CI, 2.1–23.1, respectively).ConclusionIn a Dutch cohort of overweight/obese children, Turkish children showed significantly higher prevalences of cardiometabolic risk factors relative to their peers of Moroccan descent. The prospective value of these findings needs to be established as this may warrant the need for differential ethnic-specific preventive measures.

Urinary matrix metalloproteinase-8 and-9 activities in type 2 diabetic subjects: A marker of incipient diabetic nephropathy?

Matrix metalloproteinases (MMPs) may play a pathophysiological role in the development of diabetic nephropathy (DN). We hypothesized that urinary MMP activity in patients with type 2 diabetes mellitus (T2DM) is related to a decline in renal function. We determined MMP-2, -8 and -9 activity in 24-h urine collections in relation to risk factors for DN in T2DM patients with (UA, n=27) and without albuminuria (NA, n=48) and controls (CO, n=28). MMP-8 and -9 levels were highest in UA patients (P<0.01). Of UA patients, 93% had at least one MMP increased, compared to 78% of NA patients and 46% of CO (P=0.001). Age, diabetes duration, BMI, systolic blood pressure, fasting plasma glucose, HbA1c and renal function were determinants of MMP-8 and -9 (P<0.05). In summary, MMP-8 and -9 are highest in T2DM UA patients. MMP-9, showed the strongest associations with clinical parameters related to DN.

Myeloperoxidase concentrations in EDTA-plasma of healthy subjects are discordant with concentrations in heparin-plasma and serum

OBJECTIVES To examine the effect of blood anticoagulation type on the myeloperoxidase (MPO) concentration. DESIGN AND METHODS MPO was measured in EDTA-plasma and matched heparin-plasma and serum samples collected from healthy volunteers. RESULTS MPO concentrations in heparin-plasma and serum were higher than in EDTA-plasma (both P<0.001). MPO in EDTA-plasma was not significantly correlated with MPO in either heparin-plasma or serum. CONCLUSIONS For MPO measurements, EDTA-plasma is the preferred specimen as it appears unaffected by ex vivo release of MPO from leukocytes.

Identifying the metabolic syndrome in obese children and adolescents: do age and definition matter?

OBJECTIVES To assess the prevalence of the metabolic syndrome (MetS) in overweight/obese children and adolescents of an out-patient clinic, and to compare two definitions of MetS in adolescents. METHODS In total, 528 overweight / obese children (3-16 years), of multi-ethnic origin, underwent an oral glucose tolerance test, blood collections and anthropometric measurements. In children <10 years, MetS was assessed according to child-specific cut-off values (MetS-child). In adolescents, MetS-child and MetS-adolescent (the recommendation of the International Diabetes Federation for adolescents) were compared. RESULTS The prevalence of MetS-child within the cohort (median age 11.3, range 3.1-16.4 yrs) was 18.6% (children <10 years vs. adolescents: 14.1% vs. 20.7%, P=0.073). Insulin resistance was present in 47.7% (children <10 years vs. adolescents: 21.8% vs. 60.1%, P<0.001). MetS-child was highly prevalent, and not statistically significant between age groups. In adolescents, the prevalence of MetS-adolescent was higher than MetS-child (33.2% vs. 20.7%, P<0.001). The agreement between the MetS definitions was moderate (kappa =0.51), with the agreement for the MetS-criteria for abnormal lipid levels being substantial to very good (kappa =0.71 to 0.80). CONCLUSIONS MetS-child was highly prevalent in overweight/obese children and adolescents. A higher prevalence of MetS according to adolescent- as compared to child-specific criteria was found.

Prevalence of Nonalcoholic Fatty Liver Disease and Its Association With Cardiovascular Disease Among Type 2 Diabetic Patients: Response to Targher et al.

We read with great interest the recent article by Targher et al. (1) reporting the prevalence of nonalcoholic fatty liver disease (NAFLD) and associated cardiovascular disease (CVD) risk factors in patients with type 2 diabetes. Proper identification of patients with NAFLD is of major importance for adequate treatment and reduction of CVD risk in type 2 diabetic patients. However, routine ultrasound examination of the abdomen for the screening of hepatic steatosis in combination with serologic …

Effect of three consecutive meals on the physicochemical properties of HDL and LDL in individuals with the metabolic syndrome and patients with type 2 diabetes

Background/Objectives:Postprandial hyperlipidemia, which is exaggerated and prolonged in insulin-resistant individuals, has been associated with cardiovascular disease. The objective of this study was to investigate whether and how the composition, size and function of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles are affected in the postprandial state among males with the metabolic syndrome (MetS) or type 2 diabetes (T2DM), compared with controls.Subjects/Methods:A total of 14 males with T2DM, 14 with the MetS and 14 age-matched controls were given three standardized high-fat mixed meals (900 kcal; 50-g fat, 75-g carbohydrate and 35-g protein) as breakfast, lunch and dinner. Blood sampling was performed just before each meal, and 4 and 8 h after the last meal. HDL and LDL were isolated by ultracentrifugation and analyzed for their composition, particle diameter and functional properties.Results:Postprandial triglycerides levels in plasma, HDL and LDL particles increased significantly in all groups (P<0.01). Compared with the control subjects, patients with T2DM had smaller LDL particles, and in agreement, a lower cholesterol-to-protein content in both fasting and postprandial samples. A prolonged increase in susceptibility of LDL to oxidation was found in all subjects, but was most evident in T2DM. The postprandial effect on LDL oxidation was associated with an increase in LDL triglyceride (r=0.29, P<0.05). In T2DM the anti-oxidative capacity of HDL trended to impairment after the third meal.Conclusions:Postprandial increases in triglycerides, especially in T2DM, are accompanied by pro-atherosclerotic functional changes in HDL and LDL particles.