Reduced sensitivity of the ferroportin Q248H mutant to physiological concentrations of hepcidin

Ferroportin Q248H mutation has an allele frequency of 2.2–13.4% in African populations and is associated with a mild tendency to increased serum ferritin in the general population. Some investigators have reported that ferroportin Q248H is degraded after exposure to hepcidin in exactly the same manner as wild-type ferroportin, but supraphysiological concentrations of hepcidin were used. The aim of our study was to determine whether ferroportin Q248H may have reduced sensitivity to physiological concentrations of hepcidin. The sensitivity of ferroportin Q248H to hepcidin was determined in 293T cells transiently expressing ferroportin using immunoblotting and fluorescence analysis. Ferritin concentrations were measured in these cells and also in human primary monocytes derived from humans with different ferroportin genotypes. The effect of Q248H on serum iron measures was examined in patients with sickle cell anemia. Immunoblotting and fluorescence analysis showed decreased sensitivity of ferroportin Q248H to physiological concentrations of hepcidin. Lower ferritin concentrations were observed after incubation with iron and hepcidin in 293T cells expressing ferroportin Q248H and in primary monocytes from ferroportin Q248H subjects. In sickle cell anemia, ferroportin Q248H heterozygotes had lower serum ferritin concentrations than wild-type subjects, consistent with enhanced iron release by macrophage ferroportin Q248H. A clinical benefit of ferroportin Q248H was suggested by lower echocardiographic estimates of pulmonary artery pressure in patients carrying mutant alleles. In conclusion, our results suggest that ferroportin Q248H protein is resistant to physiological concentrations of hepcidin and that this mutation has discernible effects on iron metabolism-related clinical complications of sickle cell anemia. They provide a mechanistic explanation for the effect of ferroportin Q248H on iron status in individuals of African descent and suggest that these changes in iron metabolism may be beneficial under certain disease-specific circumstances.(ClinicalTrials.gov Identifier:{"type":"clinical-trial","attrs":{"text":"NCT00011648","term_id":"NCT00011648"}}NCT00011648).     

Serum adiponectin levels, insulin resistance, and lipid profile in children born small for gestational age are affected by the severity of growth retardation at birth

OBJECTIVE: Insulin resistance has been linked to intrauterine growth retardation (IUGR); adiponectin is a protein with insulin-sensitizing properties. This study was designed to test whether being born small for gestational age (SGA) has an effect on blood levels of adiponectin and leptin, insulin resistance parameters, and lipid profile in pre-puberty, taking into consideration the severity of IUGR. METHODS: Serum levels of adiponectin, leptin, total cholesterol (t-CHOL), high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol, triglycerides, apolipoproteins A-1 (Apo A-1), Apo B and Apo E, lipoprotein(a) (Lp(a)), fasting glucose, and insulin (Ins), the homeostasis model assessment insulin resistance index (HOMA-IR) and anthropometric indices were evaluated in 70 children aged 6-8 years, born appropriate for gestational age (AGA; n = 35) and SGA (n = 35), matched for age, gender, height, and BMI. SGA children were divided into two subgroups according to the severity of IUGR: SGA<3rd percentile (n = 20), and SGA 3rd-10th percentile (n = 15). They were also subdivided in two subgroups, those with (n = 25) and those without (n = 10) catch-up growth, considering their actual height corrected for mid-parental height. RESULTS: SGA children had higher Ins and HOMA-IR than AGA children (Ins, 42 +/- 23 vs 32 +/- 11 pmol/l; HOMA-IR, 1.30 +/- 0.8 vs 0.92 +/- 0.3; P<0.05). No significant difference in serum leptin was found between the SGA and the AGA groups but adiponectin showed a trend to be higher in SGA children (13.6 +/- 5.7 vs 10.8 +/- 5.9 microg/ml respectively). SGA children without catch-up growth had higher adiponectin (15.6 +/- 8.5 microg/ml, P<0.05) than AGA children. Among the SGA children, the subgroup <3rd percentile had higher Lp(a) than the subgroup 3rd-10th percentile (P<0.05). An independent positive correlation between adiponectin and Lp(a) was observed in SGA children (R = 0.59, P<0.01). CONCLUSION: SGA children, although more insulin resistant, had similar or higher adiponectin levels than matched AGA children in pre-puberty. The severity of IUGR appears to affect their metabolic profile during childhood.     

Pleiotropic effects of intravascular haemolysis on vascular homeostasis

The breakdown of senescent or defective red blood cells releases red cell contents, especially haemoglobin, which scavenges nitric oxide (NO) and decomposes to haem and free iron. These are potent oxidants, all of which have promoted the evolution of inducible and vasculoprotective compensatory pathways to rapidly clear and detoxify haemoglobin, haem and iron. Chronic haemolytic red cell disorders as diverse as sickle cell disease, thalassaemia, unstable haemoglobinopathy, cytoskeletal defects and enzymopathies have been linked to a clinical constellation of pulmonary hypertension, priapism, leg ulceration and possibly cerebrovascular disease and thrombosis. Besides free haemoglobin, haemolysis has been associated with extracellular arginase that limits substrate availability to NO synthase, endogenous inhibitors of NO synthase activity, and inappropriate activation of haemostatic pathways. This article reviews the haemolytic disorders that have been reported to manifest vascular complications, and explores the speculative possibility that haemolysis mediates some of the vascular complications of inflammation and diabetes.     

Urinary lithogenic and inhibitory factors in preterm neonates receiving either total parenteral nutrition or milk formula

The aim of this study was to evaluate prospectively the influence of nutrition on certain factors which may inhibit or promote nephrocalcinosis in two groups of preterm infants, receiving total parenteral nutrition (TPN) and special preterm milk formula respectively, but not furosemide. A total of 37 preterm infants, 15 on TPN and 22 fed a special preterm formula were studied at the end of the 1st, 2nd and 3rd weeks of life, at which time serum and 8 h urine specimens were collected. High ratios of urinary calcium to urinary creatinine (UCa/cr), urinary oxalate to urinary creatinine (Uox/cr) and urinary calcium to urinary citrate (UCa/cit) indicates an increased risk for nephrocalcinosis while high urinary citrate to urinary creatinine (Ucit/cr) ratio indicates protection. Uox/cr increased significantly (P<0.05) in those infants fed preterm formula, from the end of 2nd week of life and was two-fold higher than in the TPN group of preterm infants (P<0.01). Ucit/cr was higher throughout the study period in the formula fed than in the TPN preterm infants. UCa/cit was five-fold higher (P<0.01) in the TPN group, by the end of the 3rd week. Urinary calcium and magnesium was similar in both groups during the study period. Two of the infants studied (5.4%), one from each group, developed nephrocalcinosis.CONCLUSION: In preterm neonates on total parenteral nutrition, urinary oxalate -to-creatinine ratio (a potent lithogenic factor) was lower and urinary citrate -to-creatinine ratio (a lithoprotective factor) also lower than in formula fed neonates. The type of feeding (total parenteral nutrition or special preterm milk formula) seems to affect urinary oxalate and citrate but not calcium and magnesium in non-furosemide treated preterm infants during the first 3 weeks of life.     

Renal venous thrombosis in an infant with predisposing thrombotic factors: color Doppler ultrasound and MR evaluation

We report a case of a neonate with hereditary thrombophilia presenting with renal venous thrombosis (RVT). Early color Doppler findings of RVT were lacking venous flow, and the arterial diastolic flow was reversed. This very high-resistance arterial flow is for the first time described in neonatal RVT. Magnetic resonance imaging showed low signal intensity of the renal pyramids on T1- and T2-weighted images, suggesting acute hemorrhage. After intravenous contrast injection, persistent cortical enhancement was observed along with lack of medullary enhancement. Despite the progressive reestablishment of some venous drainage, the kidney showed atrophy and loss of function.