Chidi Victor Nweneka

Helicobacter pylori infection and circulating ghrelin levels - A systematic review

BackgroundThe nature of the association between ghrelin, an orexigenic hormone produced mainly in the stomach, and Helicobacterpylori (H pylori), a bacterium that colonises the stomach, is still controversial. We examined available evidence to determine whether an association exists between the two; and if one exists, in what direction.MethodsWe reviewed original English language studies on humans reporting circulating ghrelin levels in H pylori infected and un-infected participants; and circulating ghrelin levels before and after H pylori eradication. Meta-analyses were conducted for eligible studies by combining study specific estimates using the inverse variance method with weighted average for continuous outcomes in a random effects model.ResultsSeventeen out of 27 papers that reported ghrelin levels in H pylori positive and negative subjects found lower circulating ghrelin levels in H pylori positive subjects; while 10 found no difference. A meta-analysis of 19 studies with a total of 1801 participants showed a significantly higher circulating ghrelin concentration in H pylori negative participants than in H pylori positive participants (Effect estimate (95%CI) = -0.48 (-0.60, -0.36)). However, eradicating H pylori did not have any significant effect on circulating ghrelin levels (Effect estimate (95% CI) = 0.08 (-0.33, 0.16); Test for overall effect: Z = 0.67 (P = 0.5)).ConclusionsWe conclude that circulating ghrelin levels are lower in H pylori infected people compared to those not infected; but the relationship between circulating ghrelin and eradication of H pylori is more complex.

Haplotype Association between Haptoglobin (Hp2) and Hp Promoter SNP (A-61C) May Explain Previous Controversy of Haptoglobin and Malaria Protection

Background Malaria is one of the strongest recent selective pressures on the human genome, as evidenced by the high levels of varying haemoglobinopathies in human populations–despite the increased risk of mortality in the homozygous states. Previously, functional polymorphisms of Hp, coded by the co-dominant alleles Hp1 and Hp2, have been variously associated with several infectious diseases, including malaria susceptibility. Methodology/Principal Findings Risk of a clinical malarial episode over the course of a malarial transmission season was assessed using active surveillance in a cohort of Gambian children aged 10–72 months. We report for the first time that the major haplotype for the A-61C mutant allele in the promoter of haptoglobin (Hp)–an acute phase protein that clears haemoglobin released from haemolysis of red cells–is associated with protection from malarial infection in older children, (children aged ≥36 months, >500 parasites/ul and temperature >37.5°C; OR = 0.42; [95% CI 0.24–0.73] p = 0.002) (lr test for interaction, <36 vs ≥36 months, p = 0.014). Protection was also observed using two other definitions, including temperature >37.5°C, dipstick positive, plus clinical judgement of malaria blinded to dipstick result (all ages, OR = 0.48, [95% CI 0.30–0.78] p = 0.003; ≥36 months, OR = 0.31, [95% CI 0.15–0.62] p = 0.001). A similar level of protection was observed for the known protective genetic variant, sickle cell trait (HbAS). Conclusions/Significance We propose that previous conflicting results between Hp phenotypes/genotypes and malaria susceptibility may be explained by differing prevalence of the A-61C SNP in the populations studied, which we found to be highly associated with the Hp2 allele. We report the -61C allele to be associated with decreased Hp protein levels (independent of Hp phenotype), confirming in vitro studies. Decreased Hp expression may lead to increased oxidant stress and increased red cell turnover, and facilitate the development of acquired immunity, similar to a mechanism suggested for sickle cell trait.

Iron delocalisation in the pathogenesis of malarial anaemia.

There is consensus that the pathophysiology of malaria-associated anaemia is multifactorial, but the precise mechanisms behind many of the haematological changes during malaria remain unclear. In this review, we attempt to build a composite picture of the pathophysiology of malarial anaemia using evidence from experimental, human and animal studies. We propose that cytokine- and hepcidin-mediated iron delocalisation, a principal mechanism in the anaemia of inflammation, plays an important role in the aetiology of malarial anaemia, and can explain some of the clinical and laboratory findings. These mechanisms interact with other aetiological determinants, such as dietary iron and micronutrient supply, helminth load, other infections and genetic variation, in determining the severity and associated features of anaemia. We suggest that iron delocalisation as a mechanism for malarial anaemia could be exploited for the development of alternative therapeutic strategies for post-malaria anaemia.

Asymptomatic malaria in the etiology of iron deficiency anemia: a nutritionist's viewpoint

An acute episode of malaria usually precipitates anemia ofavaryingseveritywhich,inextremecases,canbefatal.Thispost-malarial anemia has the characteristics of iron deficiency anemia(IDA).Itresultslargelyfromaredistributionofironbecausethereis minimal iron excretion after the lysis of infected (and unin-fected) red cells caused by malaria. Instead, the potentially toxichemoglobinreleasedwhentheerythrocyte rupturesiscomplexedto haptoglobin and hemopexin. The haptoglobin-hemoglobincomplex is recognized by specific receptors on circulating mac-rophages (CD163) and internalized. The iron-loaded macro-phages migrate to the reticuloendothelial system where theycan lodge for long periods of time. The hemopexin-heme com-plex undergoes receptor-mediated uptake by liver cells whereagain the iron can persist for a long time.Theseprocessesalsoplayamajorroleintheanemiaofchronicdiseaseandarepartofanintegratedacute-phaseresponsethathasevolved—itisassumed—tomaintainbodyironandyettopreventiron-catalyzed free-radical damage and to sequester it safely be-yond the reach of (most) potentially pathogenic bacteria. Bacter-emic septicemias are commonly precipitated by malaria (eg,reference 1) and may be a major cause of mortality. Of all theessential micronutrients, iron appears to be by far the mostcritical mediator of this battle between the human host and itspathogens and hence must be very carefully chaperoned andstored (2).Malaria is a strongly inflammatory disease, and while the in-flammationpersiststherecyclingofsequesteredironfromtheliverandmacrophagesremainsblocked(3).Intheimmediateaftermathof acute malaria it is this redistribution of body iron that is centralto the iron-limited suppression of erythropoiesis because, undernormal circumstances, ’95% of the iron supply to the erythroncomes from recycled iron and only 5% from recent absorptionfrom the diet (4). In malaria, and during early convalescence, theerythropoeitic drive usually remains high (signaled by raised er-ythropoeitin), but erythropoiesis is often, although not always,impaired [signaled by low soluble transferrin receptor (sTFR)and reticulocyte levels]. In the absence of a sufficient iron supply,there is microcytosis and an increase in the proportion of porphy-rin moieties in which zinc is substituted for iron, thus creatingelevated concentrations of zinc protoporphyrin (ZnPP). RaisedZnPP is normally interpreted as indicating iron deficiency; it isconsidered to be independent of confounding affects of inflam-mation, but in actuality reflects functional iron supply to theerythron, a subtle but important difference. Intriguingly, ZnPPmay have additional antimalarial effects (5).Afurthermechanismtodepletethesystemiccirculationofironisbyblockingintestinalabsorption.Thiscontributestothelonger-term anemia common in malaria-endemic areas, especially be-cause diets in these regions tend to contain low amounts of iron,very low amounts of heme-iron, and high amounts of phytatesand polyphenols.TracerstudiesusingFe

Haptoglobin genotype, anaemia and malaria in Gambian children

Objective  To retest our previous finding that the haptoglobin (Hp) 22 genotype is associated with seasonal anaemia, and to investigate the role of malaria in this effect.

Randomised controlled trial of weekly chloroquine to re-establish normal erythron iron flux and haemoglobin recovery in postmalarial anaemia.

Objective To determine if low-dose weekly chloroquine (CQ) therapy improves recovery from malaria-associated anaemia. Design Proof of concept randomised clinical trial. Setting West Kiang District, Lower River Region, The Gambia. Participants Children resident in participating communities, aged 12–72 months, with uncomplicated malaria identified using active case detection over two consecutive malaria transmission seasons. Interventions In 2007, eligible children were randomised to chloroquine-sulfadoxine/pyrimethamine (CQ-SP) or co-artemether (ACT) antimalarial therapy, and after parasite clearance on day 3 were subsequently re-randomised (double-blind) to weekly low-dose CQ (5 mg/kg) or placebo. In 2008, all eligible children were treated with ACT and subsequently randomised to CQ or placebo. Outcome measures The primary outcome was a change in haemoglobin from baseline (day 3 of antimalarial treatment) to day 90 in the CQ and placebo treatment arms. Secondary outcomes were changes in urinary neopterin as a marker of macrophage activation, markers of erythropoietic response and prevalence of submicroscopic parasitaemia. Change in haemoglobin in the placebo arm by initial antimalarial treatment was also assessed. Results In 2007, 101 children with uncomplicated malaria were randomised to antimalarial treatment with CQ-SP or ACT and 65 were subsequently randomised to weekly CQ or placebo. In 2008, all children received ACT antimalarial treatment and 31 were subsequently randomised to receive weekly CQ or placebo. Follow-up to day 90 was 96%. There was no effect of weekly CQ vs placebo on change in haemoglobin at day 90 (CQ+10.04 g/L (95% CI 6.66 to 13.42) vs placebo +7.61 g/L (95% CI 2.88 to 12.35)). There was no effect on the secondary outcomes assessed, or effect of initial antimalarial therapy on haemoglobin recovery. Higher day 90 haemoglobin correlated independently with older age, not being stunted, higher haemoglobin at day 0 and adequate iron status at day 3. Conclusions Weekly low-dose CQ after effective antimalarial treatment is not effective in improving recovery from postmalarial anaemia. Trial registration The clinical trial registration number is NCT00473837 (ClinicalTrials.gov).