Effects of Pubertal Status and Inflammation on the Use of Ferritin to Define Iron Deficiency in Children With Overweight or Obesity.

BACKGROUND AND AIMS: A worldwide increase in childhood overweight (OW) and obesity (OB) has been reported. OB is an inflammatory state which affects iron metabolism and the sensibility of the tests to detect iron deficiency (ID). Our aim was to evaluate the adequacy of current ferritin cut-offs to define ID in children with OW/OB. METHODS: This cross-sectional study included 152 children (54% girls) aged (median [Q1-Q3]) 11 (8-13) years with OW/OB. Complete blood count and iron metabolism were evaluated. Low ferritin, transferrin saturation (TSat), and anemia were defined by age- and sex-specific cut-offs recommended by National Guidelines. Iron intake was assessed in a subgroup (n = 80) by a 24-hour dietary recall. Analyses were made according to pubertal development and ferritin tertiles. RESULTS: The overall prevalence of low ferritin, TSat, and anemia was 2.6%, 23.8%, and 5.2%, respectively. Among pre-pubertal children (n = 87), the frequency of low TSat rose across ferritin tertiles (P < .05), whereas it decreased among pubertal children (n = 65; P < .005). Cases of anemia among pre-pubertal children were found in the highest ferritin tertile, whereas 4/6 anemia cases in pubertal children were found in the lowest ferritin tertile (<39 µg/L). Pubertal children within the lowest ferritin tertile + low TSat (n = 11) showed lower hemoglobin (-9%; P < .005) and hematocrit (-8%, P < .01) than those in the same tertile + normal TSat (n = 16). The overall prevalence of children with ferritin < 39 µg/L + low TSat was 9.2%. CONCLUSIONS: Higher ferritin cut-off values are required to define ID in children with OW/OB. Such cut-off remains to be validated in larger, multi-ethnic cohorts of children with OW/OB.

Lipoprotein alterations, hepatic lipase activity, and insulin sensitivity in subclinical hypothyroidism: response to L-T(4) treatment.

UNLABELLED: Subclinical hypothyroidism (sH) has been associated with atherosclerotic cardiovascular disease even in the absence of hypercholesterolemia. OBJECTIVE: Our study was designed to assess the hypothesis that other pro-atherogenic parameters, such as qualitative lipoprotein changes and insulin resistance, might be present in sH. DESIGN AND METHODS: Twenty-one sH women were compared to 11 female controls matched for body mass index, menopausal status, and age. Before and after 6 months of levothyroxine (L-T(4)) treatment, we determined total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), apoB levels, hepatic lipase (HL) activity in postheparin plasma samples, the chemical composition and copper-induced oxidation in isolated LDL and homeostasis model assessment (HOMA), quantitative insulin sensitivity check index, and insulinogenic index. MAIN OUTCOME: Lipid profiles were similar between the two groups. No differences in LDL oxidability or the insulin sensitivity assessment parameters were found. HL activity was significantly lower in the sH patients: median (range), 13.1 (2.5-26.7) vs. 18.7 (7.9-28.1) micromol free fatty acids/mL, p < 0.04. The LDL-cholesterol/LDL-TG ratio was decreased in sH: 3.9 (1.8-5.5) vs. 4.7 (3.5-6.8), p < 0.02. HL negatively correlated with thyroid-stimulating hormone (TSH) levels (r = - 0.504, p < 0.01) and positively with LDL-cholesterol/LDL-TG (r = 0.46, p < 0.02). Posttreatment results for all these parameters did not differ significantly compared to baseline. CONCLUSIONS: Increased levels of TSH are associated to a decrease in HL activity, explaining our findings of an LDL particle rich in TG. This qualitative lipoprotein alteration suggests a pro-atherogenic pattern in sH. Treatment with L-T(4), however, did not correct the basal lipid derangement.

HDL capacity to inhibit LDL oxidation in well-trained triathletes.

Physical activity is known to play a cardioprotective role. Nevertheless, a paradox seems to arise when considering that aerobic exercise enhances oxidative stress. In previous works, we showed that free radical formation during physical activity was counteracted by an increase in antioxidant defenses. Low density lipoprotein (LDL) oxidation is a crucial step in atherosclerosis, process that can be inhibited by high density lipoprotein (HDL) through its oxidable components or associated enzymes like paraoxonase (PON) and platelet-activating factor acetylhydrolase (PAF-AH). In this study, we evaluated copper-induced oxidation in isolated LDL and HDL fractions, and the effect of HDL on LDL oxidation in samples from well trained amateur athletes who were participating in an ultra-distance triathlon (n=18) in comparison with healthy sedentary controls (n=18). PON and PAF-AH activities and PON phenotype were also evaluated. The oxidability of isolated lipoproteins, as well as HDL antioxidant capacity, was similar in both groups of subjects. After classification by paraoxonase phenotype, only sportsmen belonging to the QR phenotype showed higher HDL susceptibility to in vitro oxidation (thiobarbituric reactive substances, TBARS) than controls (p<0.05). HDL oxidability exhibited a positive correlation with its triglyceride content (r=0.58; p<0.01). Similarly, HDL capacity to inhibit LDL oxidation was increased in athletes (p<0.05) which was positively associated with HDL oxidability (HDL-TBARS: r=0.55, p<0.005; HDL-lag time: r=0.45, p<0.01; HDL-D max: r=0.35, p<0.05). In conclusion, regular aerobic exercise was associated to a more efficient antioxidant function played by HDL from PON-QR carriers, which could constitute an adaptive response to the increased oxidative stress.

Increased MMP-2 in healthy postmenopausal women.

BACKGROUND: Matrix metalloproteases 2 (MMP-2) and 9 (MMP-9) are involved in the atherosclerosis process. The objective of the study was to evaluate MMP-2 and MMP-9 activities and other circulating inflammatory factors in healthy postmenopausal women (PMW) as a model of subclinical atherosclerosis. METHODS: Twenty-three PMW and 13 premenopausal women (PreMW) were selected following established criteria. The main measurements in plasma samples were: lipid-lipoprotein profile, high-sensitivity C-reactive protein (hs-CRP) (immunoturbidimetry), soluble vascular cellular adhesion molecules (sVCAM-1) enzyme-linked immunosorbent assay and MMP activity by zymography. RESULTS: The relative areas of MMP-2 were increased in PMW: 1.1 (0.1) versus 0.6 (0.05), P < 0.02. MMP-9 was only detected in three PMW and one PreMW. MMP-2 correlated with HDL-cholesterol (r = -0.51), triglycerides (r = 0.67), apolipoprotein B (r = 0.47), hs-CRP (r = 0.42), homeostasis model assessment (r = 0.53) and waist circumference (r = 0.40), at least P < 0.02. sVCAM-1 showed no difference between groups: 28.7 (5.5) versus 35.5 (20) ng/mL, but correlated with MMP-2 and hs-CRP (r = 0.46 and r = 0.48 respectively, P < 0.05). CONCLUSIONS: In postmenopause, the increase in MMP-2 reflects the systemic specific inflammatory process that accompanies atherogenesis.

Metalloproteases 2 and 9, Lp-PLA(2) and lipoprotein profile in coronary patients.

BACKGROUND AND AIMS: Many studies suggest that the different steps of the atherosclerotic process may be mediated by metalloproteases (MMPs). MMP-9 and MMP-2, which are highly expressed in the vulnerable regions of the atherosclerotic plaques, have been suggested to be causally involved in plaque rupture. In another manner linked with LDL, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) hydrolyzes phospholipids generating proinflammatory and proatherogenic products. Our aim was to evaluate plasma activity of MMP-2 and 9, as well as Lp-PLA(2), in subjects with coronary artery stenosis in comparison with controls and to correlate these activities with lipoprotein profile and general biomarkers of inflammation. METHODS: Forty two subjects who had undergone coronary angiography were divided into two groups: patients with coronary vessels with at least 45% stenosis (CAD [coronary artery disease], n = 24) and patients without angiographically detectable coronary artery disease (controls, n = 18). Plasma activity of MMP-2 and MMP-9 was measured and correlated with markers of systemic inflammation (hs-CRP), subendothelial inflammation (Lp-PLA(2)) and lipoprotein profile. RESULTS: Plasma activity of both MMPs was consistently higher in patients than in controls (p <0.01). Pro-MMP-2 (r = 0.34, p <0.01) and MMP-9 (r = 0.51, p <0.02) activities correlated with apoprotein B. Pro-MMP-2 correlated with hs-CRP (r = 0.47, p <0.01) and inversely with HDL cholesterol (r = -0.35, p <0.02). No differences were observed in Lp-PLA(2) between patients and controls (15.2 +/- 4.0 vs. 15.4 +/- 4.5 micromol/mL/h, p = NS, respectively), and no correlation was observed with MMPs. CONCLUSIONS: MMP activity was higher in CAD than in controls. The correlation observed between pro-MMP-2 and high-sensitive C-reactive protein (hs-CRP) may be due to specific systemic inflammatory processes. No correlation was observed between Lp-PLA(2) and MMPs.

Increased plasma activity of metalloproteinase 2 in women with metabolic syndrome.

Metalloproteinases (MMPs) play a significant role in vascular remodeling, and they have been suspected to be partly responsible for the pathogenesis of cardiovascular disease. Metalloproteinases have been reported to be increased in atherosclerosis and type 2 diabetes mellitus; however, so far they have not been evaluated in metabolic syndrome (MetS). Plasma activity of MMP-2 and MMP-9, high-sensitivity C-reactive protein concentration, dense low-density lipoprotein, and insulin-resistance markers were measured in 38 nondiabetic women with (n = 19) and without (n = 19) MetS. Women with MetS had significantly higher plasma activity of MMP-2 than controls (median [range], 1.3 [0.4-3.1] vs 0.7 [0.1-1.9]; P = .001). MMP-2 activity positively correlated with waist, homeostasis model assessment, and high-sensitivity C-reactive protein (P < .02) as well as with apolipoprotein B, dense low-density lipoprotein, triglycerides/high-density lipoprotein cholesterol index (P < .001) and negatively with high-density lipoprotein cholesterol (P < .002). Our finding of increased plasma activity of MMP-2 in women with MetS is important because they fit in with an early stage of cardiovascular disease; and measurement of soluble molecules may improve the risk assessment, early diagnosis, and prognosis of cardiovascular disease.

Factores circulantes de injuria endotelial y procesos subendoteliales en mujeres postmenopáusicas sanas / Endothelial injuring factors and subendothelial events in healthy postmenopausal women

La concentración elevada de lipoproteínas aterogénicas con apo B en mujeres posmenopáusicas (MPM), es un componente importante del mecanismo multifactorial causante de la enfermedad coronaria. En MPM sanas (n=30) en comparación con premenopáusicas (MpreM) (n=28), se evaluó el perfil lipoproteico incluyendo apoproteínas A-I y B, LDL pequeña y densa, composición y oxidabilidad de LDL, proteína transportadora de colesterol esterificado y lipasa hepática. Se determinaron los siguientes factores emergentes: homocisteína, fosfolipasa A2, ferritina, PCR-hs (alta sensibilidad) y fibronectina proveniente de la matriz extracelular. La insulino-resistencia fue evaluada por la circunferencia de cintura, el índice HOMA y el índice triglicéridos/colesterol-HDL. El índice de riesgo apo B/apoA-I fue significativamente mayor en MPM (p<0,0001). MPM presentaron mayor proporción de LDL pequeña y densa, la cual correlacionó con el aumento de actividad de lipasa hepática (p<0,005), y con marcadores de insulino-resistencia (p<0,05). Fosfolipasa A2 (p<0,05), homocisteína (p<0,005), ferritina (p<0,0001), PCR-hs (p<0,005) y fibronectina (p<0,05)) fueron mayores en MPM. La oxidabilidad de LDL no mostró diferencias significativas pero correlacionó positivamente con LDL pequeña y densa (p<0,01), fosfolipasa A2 (p<0,05), homocisteína (p<0,05), PCR-hs (p<0,04), fibronectina (p<0,05) y cintura (p<0,02). Luego de ajustar por la condición menopáusica, edad y cintura, la oxidabilidad de LDL permaneció asociada con LDL pequeña y densa (b:0,36, p=0,027), homocisteína (b:0,36, p<0,038), fibronectina (b:0,41 p=0,05) y cintura (b:0,35, p=0,047). En este estudio, la interacción de factores de riesgo aterogénico clásicos y no tradicionales sugiere una secuencia de eventos que comienzan con la injuria endotelial causada por homocisteína y LDL pequeña y densa, que penetra en subendotelio donde su oxidación es favorecida por la homocisteína. Se produciría un proceso inflamatorio, que cursa con aumento de PCR y ferritina. La fosfolipasa A2, proveniente de macrófagos, atravesaría el endotelio unida a la LDL modificada, y promueve la liberación de fibronectina desde la matriz extracelular. La estrecha interacción entre la injuria endotelial, inflamación e insulino-resistencia se observaría desde estadíos subclínicos de aterosclerosis en MPM sanas.

In postmenopausal women (PMW), high concentrations of atherogenic apoB lipoproteins is an important component of the multifactorial mechanism underlying a higher risk of coronary artery disease, as compared with premenopausal women (PreMW). Lipoprotein pattern, including apopoproteins A-I and B, LDL chemical composition and small dense LDL (sdLDL), hepatic lipase activity, circulating cholesterol transfer protein and LDL oxidability were assessed in PMW (n=30) in comparison to PreMW (n=28). The following endothelial injuring factors were measured: homocysteine, lipoprotein binding phospholipase A2 (LpPLA2), ferritin, hs-CRP and fibronectin coming from extracellular vascular matrix. Insulin-resistance was evaluated by waist circumference, HOMA and triglyceride/HDL-cholesterol. PMW showed higher apoB/apoA-I (p<0.0001) and a higher proportion of sdLDL which showed significant correlations with the increase in hepatic lipase activity (p<0.005) and insulin-resistance markers (p<0.05). LpPLA2 (p<0.05), homocysteine (p<0.005), hs-CRP (p<0.005), fibronectin (p<0.05) and ferritin (p<0.0001) were elevated in PMW. LDL oxidability showed no differences between groups, but was positively correlated with waist (p<0.02), homocysteine (p<0.05), fibronectin (p<0.05), hs-CRP (p<0.04), LpPLA2 (p<0.05) and sdLDL (p<0.01). After adjusting by age, menopausal condition and waist, LDL oxidability remained associated with homocysteine (b: 0,36) p<0,038), sdLDL (b: 0.36, p=0.027), waist (b: 0.35, p=0.047) and fibronectin (b: 0,41 p=0.05). In this study, the interaction of classic and emerging atherogenic risk factors would suggest a sequence of events starting with endothelial damage caused by homocysteine and sdLDL, promoting its passage into the subendothelial space where it is oxidatively modified, enhanced by homocysteine. The above mentioned inflammatory process takes place with an increase in circulating hs-CRP and ferritin. LpPLA2, coming from macrophages, passes through the endothelium bound to modified LDL, promoting a release of fibronectin from the subendothelial extracellular matrix. Results suggest that the close interaction among endothelial injury, inflammation and insulin resistance can be observed since subclinical atherosclerosis states in healthy PMW.