Hepcidin-mediated hypoferremic response to acute inflammation requires a threshold of Bmp6/Hjv/Smad signaling.
Fillebeen Carine,Wilkinson Nicole,Charlebois Edouard,Katsarou Angeliki,Wagner John,Pantopoulos Kostas
Systemic iron balance is controlled by hepcidin, a liver hormone that limits iron efflux to the bloodstream by promoting degradation of the iron exporter ferroportin in target cells. Iron-dependent hepcidin induction requires hemojuvelin (HJV), a bone morphogenetic protein (BMP) coreceptor that is disrupted in juvenile hemochromatosis, causing dramatic hepcidin deficiency and tissue iron overload. Hjv mice recapitulate phenotypic hallmarks of hemochromatosis but exhibit blunted hepcidin induction following lipopolysaccharide (LPS) administration. We show that Hjv mice fail to mount an appropriate hypoferremic response to acute inflammation caused by LPS, the lipopeptide FSL1, or infection because residual hepcidin does not suffice to drastically decrease macrophage ferroportin levels. Hfe mice, a model of milder hemochromatosis, exhibit almost wild-type inflammatory hepcidin expression and associated effects, whereas double HjvHfe mice phenocopy single Hjv counterparts. In primary murine hepatocytes, Hjv deficiency does not affect interleukin-6 (IL-6)/Stat, and only slightly inhibits BMP2/Smad signaling to hepcidin; however, it severely impairs BMP6/Smad signaling and thereby abolishes synergism with the IL-6/Stat pathway. Inflammatory induction of hepcidin is suppressed in iron-deficient wild-type mice and recovers after the animals are provided overnight access to an iron-rich diet. We conclude that Hjv is required for inflammatory induction of hepcidin and controls the acute hypoferremic response by maintaining a threshold of Bmp6/Smad signaling. Our data highlight Hjv as a potential pharmacological target against anemia of inflammation.
Effects of IL-10 on iron metabolism in LPS-induced inflammatory mice via modulating hepcidin expression.
Huang P,Wang J,Lin X,Yang F-F,Tan J-H
European review for medical and pharmacological sciences
OBJECTIVE:Body's iron metabolism is at one dynamic balance status, and abnormal iron metabolism may lead to renal anemia. Inflammation stimuli may lead to abnormal iron metabolism and aggravation of chronic failure anemia. Hepcidin can regulate iron metabolic homeostasis, further mediating renal anemia. Interleukin-10 (IL-10) is an inflammatory inhibitor, but with an unclear function in the regulation of hepcidin expression. MATERIALS AND METHODS:BALB/c mice were randomly assigned into three groups: control group; lipid polysaccharide (LPS) group, which received 0.1 mg/kg LPS via tail veins; IL-10 group with 0.2 mg/kg IL-10 injection after LPS. Red blood cell count (RBC), hemoglobulin (Hb), hematocrit (HCT), mean corpuscular volume (MCV) and iron content in hemoglobulin were measured. Real-time PCR quantified hepcidin mRNA expression in all groups. Enzyme linked immunosorbent assay (ELISA) tested serum hepcidin, IL-6 and tumor necrosis factor-α (TNF-α) levels. Western blot analyzed expression of mouse transferrin receptor 2 (TfR2) and hepcidin signal pathway molecule STAT3. RESULTS:LPS model group had lower RBC, Hb, HCT, MCV and iron content in Hb, plus elevated hepcidin, IL-6, TNF-α, TfR2 and STAT3 expression (p < 0.05 compared to the control group). IL-10 treatment group significantly facilitated RBC, Hb, HCT, MCV and Hb iron contents in LPS-induced inflammatory model mice, which also had lower hepcidin, IL-6, TNF-α, TfR2 or STAT3 expression (p < 0.05 compared to LPS group). CONCLUSIONS:IL-10 can improve iron metabolism and alleviate anemia via suppressing inflammatory factor, modulating STAT3 signal pathway, down-regulating hepcidin expression and inhibiting TfR expression.
Increased hepcidin in hemorrhagic plaques correlates with iron-stimulated IL-6/STAT3 pathway activation in macrophages.
Li Bicheng,Gong Jie,Sheng Siqi,Lu Minqiao,Guo Shuyuan,Zhao Xuezhu,Zhang Haiyu,Wang Huan,Tian Zhen,Tian Ye
Biochemical and biophysical research communications
Intraplaque hemorrhage (IPH) promotes the rapid progression of atherosclerotic plaques, resulting in cardiovascular events in a short time. Hepcidin increases iron retention and exerts proinflammatory effects in plaques. However, hepcidin expression levels in hemorrhagic plaques remain unknown. In the present study, we evaluated hepcidin expression in hemorrhagic plaques and the underlying mechanism. To investigate hepcidin expression in hemorrhagic plaques, carotid artery plaques were collected from patients undergoing carotid endarterectomy (CEA) and apolipoprotein E-deficient mice. The hepcidin expression level was increased in the area of IPH and positively correlated with the amount of hemorrhage as shown by immunohistochemistry. Hepcidin expression in macrophages within human plaques was confirmed by immunofluorescence. Furthermore, ferric ammonium citrate (FAC) was found to induce hepcidin and interleukin-6 (IL-6) expression in THP-1 macrophages and mouse peritoneal macrophages. Subsequently, activation of the IL-6/signal transducer and activator of transcription (STAT) 3 pathway was observed in rabbit hemorrhagic plaques. Macrophages were pretreated with antibodies that block IL-6/IL-6R interactions or STAT3 activation and dimerization inhibitor (STATTIC), and the results indicated that FAC induced hepcidin expression through the IL-6/STAT3 pathway. In conclusion, our data indicate that hepcidin levels are increased in hemorrhagic plaques, which correlates with iron-stimulated IL-6/STAT3 pathway activation in macrophages. Therefore, inhibition of the IL-6/STAT3 pathway may be a potential strategy to reduce hepcidin expression and further stabilize hemorrhagic plaques.
A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin.
Kim Airie,Fung Eileen,Parikh Sona G,Valore Erika V,Gabayan Victoria,Nemeth Elizabeta,Ganz Tomas
Anemia is a common complication of infections and inflammatory diseases, but the few mouse models of this condition are not well characterized. We analyzed in detail the pathogenesis of anemia induced by an injection of heat-killed Brucella abortus and examined the contribution of hepcidin by comparing wild-type (WT) to iron-depleted hepcidin-1 knockout (Hamp-KO) mice. B abortus-treated WT mice developed severe anemia with a hemoglobin nadir at 14 days and partial recovery by 28 days. After an early increase in inflammatory markers and hepcidin, WT mice manifested hypoferremia, despite iron accumulation in the liver. Erythropoiesis was suppressed between days 1 and 7, and erythrocyte destruction was increased as evidenced by schistocytes on blood smears and shortened red blood cell lifespan. Erythropoietic recovery began after 14 days but was iron restricted. In B abortus-treated Hamp-KO compared with WT mice, anemia was milder, not iron restricted, and had a faster recovery. Similarly to severe human anemia of inflammation, the B abortus model shows multifactorial pathogenesis of inflammatory anemia including iron restriction from increased hepcidin, transient suppression of erythropoiesis, and shortened erythrocyte lifespan. Ablation of hepcidin relieves iron restriction and improves the anemia.
Vitamin A deficiency modulates iron metabolism via ineffective erythropoiesis.
da Cunha Marcela S B,Siqueira Egle M A,Trindade Luciano S,Arruda Sandra F
The Journal of nutritional biochemistry
Vitamin A modulates inflammatory status, iron metabolism and erythropoiesis. Given that these factors modulate the expression of the hormone hepcidin (Hamp), we investigated the effect of vitamin A deficiency on molecular biomarkers of iron metabolism, the inflammatory response and the erythropoietic system. Five groups of male Wistar rats were treated: control (AIN-93G), the vitamin A-deficient (VAD) diet, the iron-deficient (FeD) diet, the vitamin A- and iron-deficient (VAFeD) diet or the diet with 12 mg atRA/kg diet replacing all-trans-retinyl palmitate by all-trans retinoic acid (atRA). Vitamin A deficiency reduced serum iron and transferrin saturation levels, increased spleen iron concentrations, reduced hepatic Hamp and kidney erythropoietin messenger RNA (mRNA) levels and up-regulated hepatic and spleen heme oxygenase-1 gene expression while reducing the liver HO-1 specific activity compared with the control. The FeD and VAFeD rats exhibited lower levels of serum iron and transferrin saturation, lower iron concentrations in tissues and lower hepatic Hamp mRNA levels compared with the control. The treatment with atRA resulted in lower serum iron and transferrin concentrations, an increased iron concentration in the liver, a decreased iron concentration in the spleen and in the gut, and decreased hepatic Hamp mRNA levels. In summary, these findings suggest that vitamin A deficiency leads to ineffective erythropoiesis by the down-regulation of renal erythropoietin expression in the kidney, resulting in erythrocyte malformation and the consequent accumulation of the heme group in the spleen. Vitamin A deficiency indirectly modulates systemic iron homeostasis by enhancing erythrophagocytosis of undifferentiated erythrocytes.
Vitamin A deficient mice exhibit increased viral antigens and enhanced cytokine/chemokine production in nasal tissues following respiratory virus infection despite the presence of FoxP3+ T cells.
Penkert Rhiannon R,Surman Sherri L,Jones Bart G,Sealy Robert E,Vogel Peter,Neale Geoffrey,Hurwitz Julia L
The World Health Organization (WHO) estimates that 250 million children under the age of five suffer from vitamin A deficiencies (VAD). Individuals with VAD experience higher rates of mortality and increased morbidity during enteric and respiratory infections compared with those who are vitamin A sufficient. Previously, our laboratory has demonstrated that VAD mice have significantly impaired virus-specific IgA and CD8(+) T-cell responses in the airways. Here, we demonstrate that VAD mice experience enhanced cytokine/chemokine gene expression and release in the respiratory tract 10 days following virus infection compared with control vitamin A sufficient animals. Cytokines/chemokines that are reproducibly up-regulated at the gene expression and protein levels include IFNγ and IL-6. Despite previous indications that cytokine dysregulation in VAD animals might reflect low forkhead box P3 (FoxP3)-positive regulatory T-cell frequencies, we found no reduction in FoxP3(+) T cells in VAD respiratory tissues. As an alternative explanation for the high cytokine levels, we found that the extent of virus infection and the persistence of viral antigens were increased on day 10 post-infection in VAD animals compared with controls, and consequently that respiratory tract tissues had an increased potential to activate virus-specific T cells. Results encourage cautious management of viral infections in patients with VAD, as efforts to enhance FoxP3(+) T cell frequencies and quell immune effectors could potentially exacerbate disease if the virus has not been cleared.
Effect of baseline micronutrient and inflammation status on CD4 recovery post-cART initiation in the multinational PEARLS trial.
Shivakoti Rupak,Ewald Erin R,Gupte Nikhil,Yang Wei-Teng,Kanyama Cecilia,Cardoso Sandra W,Santos Breno,Supparatpinyo Khuanchai,Badal-Faesen Sharlaa,Lama Javier R,Lalloo Umesh,Zulu Fatima,Pawar Jyoti S,Riviere Cynthia,Kumarasamy Nagalingeswaran,Hakim James,Pollard Richard,Detrick Barbara,Balagopal Ashwin,Asmuth David M,Semba Richard D,Campbell Thomas B,Golub Jonathan,Gupta Amita,
Clinical nutrition (Edinburgh, Scotland)
BACKGROUND & AIMS:Nutritional deficiency and inflammation may impact CD4+ T cell recovery during combination antiretroviral therapy (cART), particularly in resource-limited settings where malnutrition is prevalent. The aim of this study was to investigate the relationship of micronutrient and inflammation biomarkers to CD4 recovery after cART initiation. METHODS:We conducted a secondary analysis of a random sub-cohort sample (n = 270) from a multinational randomized trial of cART regimen efficacy among 1571 cART-naïve adults. We measured pre-cART serum levels of micronutrients (Vitamin A, B, B, D, total carotenoids, selenium, and iron) and inflammation (C-reactive protein, soluble CD14 (sCD14), IFNγ, TNFα, Interleukin-6, and C-X-C motif chemokine 10 (CXCL10/IP10), EndoCab (IgM)) biomarkers. Biomarker status (i.e. micronutrient deficiency vs. sufficiency and elevated vs. low inflammation) was defined using established cutoffs or quartiles. Mixed-effects linear regression models were used to determine the association of baseline (pre-cART) concentrations of individual biomarkers with CD4 recovery through 96 weeks post-cART initiation. RESULTS:In models adjusting for time-dependent viral load and baseline CD4 count, age, sex, body mass index, country, treatment regimen, anemia and hypoalbuminemia status, pre-cART vitamin D deficiency was associated with lower CD4 recovery (-14.9 cells/mm, 95% CI: -27.9, -1.8) compared to sufficiency. In contrast, baseline selenium deficiency (20.8 cells/mm, 95% CI: 3.3, 38.3), vitamin A deficiency (35.9 cells/mm, 95% CI: 17.6, 54.3) and high sCD14 (23.4 cells/mm, 95% CI: 8.9, 37.8) were associated with higher CD4 recovery compared to sufficient/low inflammation status. CONCLUSIONS:In summary, baseline vitamin D deficiency was associated with diminished CD4 recovery after cART initiation; impaired CD4 recovery may contribute to the poor clinical outcomes recently observed in individuals with vitamin D deficiency. Vitamin A, selenium and sCD14 were associated with CD4 recovery but future studies are needed to further explore these relationships.
Vitamin D protects against necrotising enterocolitis in newborn mice by activating the ERK signalling pathway.
Lyu Chunmei,Jiang Suhua,Kong Muxian,Chen Xiaoqian,Zhang Li
Molecular medicine reports
Necrotising enterocolitis (NEC) is a serious intestinal disease that occurs in the neonatal period. The present study aimed to investigate the protective effect of vitamin D on NEC and the underlying mechanisms. Artificial feeding and hypoxia‑cold stimulation were used to establish a mouse NEC model. IEC‑6 cells were treated with lipopolysaccharide (LPS) to establish the in vitro NEC model. Changes in the levels of interleukin (IL)‑6, IL‑1β and tumour necrosis factor (TNF)‑α, and activities of malondialdehyde (MDA) and glutathione peroxidase (GPx) were investigated via ELISA kits. In addition, mRNA expression of IL‑6, IL‑1β and TNF‑α and protein expression of phosphorylated (p)‑ERK1/2, Ki67, cleaved caspase‑3 and Bcl‑2 in intestinal tissues were determined via reverse transcription‑quantitative PCR and western blotting. Cell proliferation and apoptosis were also analysed via MTT assay and flow cytometry. In NEC mice, vitamin D reduced intestinal tissue damage, decreased the mRNA expression of IL‑6, IL‑1β and TNF‑α, and decreased the protein expression of cleaved caspase‑3 and MDA. Whereas, vitamin D increased the protein expression of Bcl‑2 and Ki67 and GPx, as well as the p‑ERK1/2/ERK1/2 ratio, in NEC mice. Furthermore, vitamin D improved cell viability, increased the ratio of p‑ERK1/2/ERK1/2, inhibited apoptosis, and decreased the mRNA expression of IL‑6, IL‑1β and TNF‑α in LPS‑treated IEC‑6 cells. The dual‑specificity mitogen‑activated protein kinase kinase inhibitor PD98059 reversed the effects of vitamin D on the proliferation, apoptosis and inflammation of LPS‑treated IEC‑6 cells. Overall, vitamin D relieved NEC in mice. Vitamin D promoted proliferation, and inhibited apoptosis and inflammation of LPS‑treated IEC‑6 cells by activating the ERK signalling pathway.
Vitamin D inhibits palmitate-induced macrophage pro-inflammatory cytokine production by targeting the MAPK pathway.
Li Wei,Liu Zhuo,Tang Renqiao,Ouyang Shengrong,Li Sen,Wu Jianxin
Vitamin D insufficiency is associated with chronic inflammatory diseases. However, the mechanism by which vitamin D reduces obesity-related inflammation remains poorly understood. In this study, we investigated the inhibitory effects of vitamin D on palmitate-induced inflammatory response in macrophages and explored the potential mechanisms of vitamin D action. The effect of vitamin D on the expression of inflammatory factors induced by palmitate, a saturated fatty acid, was investigated using human THP-1 macrophages and murine RAW 264.7 cells. To elucidate the mechanism by which vitamin D affects palmitate-induced inflammatory cytokine production, we investigated the activity of stress kinase-related proteins. Palmitate significantly increased TNF-α and IL-6 expression and secretion in THP-1 and RAW 264.7 macrophages. Treatment with the active form of vitamin D inhibited palmitate-induced TNF-α and IL-6 production in macrophages. Furthermore, vitamin D significantly reduced palmitate-stimulated activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2). The mitogen-activated protein kinase signaling pathway partly accounts for the induction of pro-inflammatory cytokines by palmitate. Our data suggest that the attenuation of palmitate-induced TNF-α and IL-6 gene expression and protein secretion by vitamin D are associated with reduced activation of JNK and ERK1/2.
Effects of vitamin D3 on selected biochemical parameters of nutritional status, inflammation, and cardiovascular disease in patients undergoing long-term hemodialysis.
Bednarek-Skublewska Anna,Smoleń Agata,Jaroszyński Andrzej,Załuska Wojciech,Ksiazek Andrzej
Polskie Archiwum Medycyny Wewnetrznej
INTRODUCTION:Vitamin D3 has diverse biological effects extending beyond the maintenance of calcium and phosphorus homeostasis and ensuring the proper functioning of the body. OBJECTIVES:This study evaluated the levels of vitamin D3 and its association with nutritional status, immunological activity, and selected markers of cardiovascular disease in patients on long-term hemodialysis (HD). PATIENTS AND METHODS:We measured 25-hydroxyvitamin D3 (25(OH)D3) levels in a group of 84 patients (mean age, 65 years; average time on dialysis, 32.5 months) and investigated correlations between 25(OH)D3 levels and the following parameters: albumin, body mass index, hemoglobin (Hb), interleukin 6 (IL-6), interleukin 10, C-reactive protein, asymmetric dimethylarginine (ADMA), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and comorbidity score. RESULTS:A mean 25(OH)D3 level was 15.4 +/-7.2 ng/ml and only 5% of patients had 25(OH)D3 levels above the normal value of 30 ng/ml. There was no statistically significant difference in 25(OH)D3 levels between women and men (P = 0.06). A negative correlation was observed between 25(OH)D3 and IL-6 (R = -0.31, P = 0.009) and ADMA (R = -0.26, P = 0.03), as well as a positive correlation between 25(OH)D3 and Hb (R= 0.21, P = 0.05). There was no association between 25(OH)D3 levels and nutritional status. CONCLUSIONS:A significant vitamin D3 deficiency observed in the majority of patients undergoing long-term HD contributes to the development of chronic inflammation, anemia, and indirectly, to endothelial cell injury.
Targeting the hepcidin-ferroportin axis to develop new treatment strategies for anemia of chronic disease and anemia of inflammation.
Sun Chia Chi,Vaja Valentina,Babitt Jodie L,Lin Herbert Y
American journal of hematology
Anemia of chronic disease (ACD) or anemia of inflammation is prevalent in patients with chronic infection, autoimmune disease, cancer, and chronic kidney disease. ACD is associated with poor prognosis and lower quality of life. Management of ACD using intravenous iron and erythropoiesis stimulating agents are ineffective for some patients and are not without adverse effects, driving the need for new alternative therapies. Recent advances in our understanding of the molecular mechanisms of iron regulation reveal that increased hepcidin, the iron regulatory hormone, is a key factor in the development of ACD. In this review, we will summarize the role of hepcidin in iron homeostasis, its contribution to the pathophysiology of ACD, and novel strategies that modulate hepcidin and its target ferroportin for the treatment of ACD.
Vitamin D status is associated with hepcidin and hemoglobin concentrations in patients with severe traumatic injury.
Apple Camille G,Miller Elizabeth S,Kannan Kolenkode B,Stortz Julie A,Cox Michael,Loftus Tyler J,Parvataneni Hari K,Patrick Matthew,Hagen Jennifer E,Brakenridge Scott,Efron Philip A,Mohr Alicia M
The journal of trauma and acute care surgery
BACKGROUND:Severe traumatic injury leads to persistent injury-associated anemia that is associated with hypercatecholaminemia, systemic inflammation, increased hepcidin, and a functional iron deficiency. Vitamin D has been shown to reduce proinflammatory cytokines and hepcidin concentrations. This study aimed to investigate the association of vitamin D status with inflammation, iron biomarkers, and anemia following blunt trauma. METHODS:A prospective observational cohort study comparing blunt trauma patients (n = 45) with elective hip replacement patients (n = 22) and healthy controls (n = 8) was performed. Bone marrow ferroportin, transferrin receptor, and erythroferrone expression was measured using quantitative polymerase chain reaction (qPCR). Plasma was assessed for systemic inflammation, erythropoietin (EPO), iron regulation, and vitamin D (25-OH) concentrations using enzyme-linked immunosorbent assay. Hemoglobin was measured on the day of discharge. RESULTS:Compared with hip replacement, trauma patients had higher plasma interleukin-6 (90.1 vs. 3.8 pg/mL), C-reactive protein (6,223 vs. 2,612 ng/mL), and hepcidin (79.3 vs. 21.2 ng/mL) concentrations. Trauma patients had lower vitamin D (25-OH) (12.8 vs. 18.1 ng/mL) and iron (23.5 vs. 59.9 μg/mL) levels compared with hip replacement patients. Despite the higher hepcidin EPO levels, bone marrow erythroferrone expression was increased 69% following trauma. CONCLUSION:Following elective hip replacement, patients did have anemia and impaired iron homeostasis without a significant change in inflammatory biomarkers, EPO, and vitamin D status. Vitamin D status did correlate with systemic inflammation, iron dysfunction, and persistent injury-associated anemia following severe blunt trauma. Further research is needed to determine whether supplementation with vitamin D in the trauma population could improve the persistent injury-associated anemia. LEVEL OF EVIDENCE:Prospective study, prognostic, level III.
Relationship between serum 25-hydroxyvitamin D and inflammatory cytokines in paediatric sickle cell disease.
Adegoke Samuel Ademola,Smith Olufemi Samuel,Adekile Adekunle D,Figueiredo Maria Stella
BACKGROUND:Alteration in the concentration of inflammatory cytokines may contribute to pathogenesis in sickle cell anaemia (SCA). Vitamin D may suppress pro-inflammatory cytokines and enhance anti-inflammatory cytokines. OBJECTIVE:To compare steady state levels of pro-and anti-inflammatory cytokines of Nigerian SCA children with age- and sex-matched healthy controls, and determine the relationship with 25-hydroxyvitamin-D (25-OHD). Effects of three months of vitamin D supplementation on cytokines of SCA children with suboptimal 25-OHD were also evaluated. METHODS:Serum 25-OHD, IL-1β, 2, 6, 8, 11, 12, 13, 17, 18 of 95 SCA children and 75 matched controls were determined using HPLC. The 12 SCA children with suboptimal 25-OHD received 2000IU of vitamin D daily for 3months, and their post supplementation cytokines and 25-OHD levels were compared with the baseline values. RESULTS:IL-2, 6, 8, 12, 17 and 18 were higher in SCA children than the controls (p≤0.001), but no significant variation in IL-11 and 13 (p=0.131 and 0.057 respectively). Patients with suboptimal serum 25-OHD had higher IL-6, 8 and 18 (p=0.003, 0.010 and 0.002 respectively) and lower levels of IL-11 (p=0.005). Significant positive treatment effects were observed: post-supplementation, serum 25-OHD increased by 23.3ng/mL, p<0.001; proinflammatory cytokines IL-2, 6, 8, 17 and 18 (p<0.001) were reduced and anti-inflammatory cytokine IL-11 was increased, p<0.001. CONCLUSIONS:Suboptimal 25OHD is associated with enhanced levels of pro-inflammatory markers in children with SCA. Three months of daily vitamin D supplementation reversed the trend. Hence; Vitamin D supplementation may reduce the inflammatory milieu and serve as an anti-inflammatory agent in the management of SCA.
Vitamin D Decreases Hepcidin and Inflammatory Markers in Newly Diagnosed Inflammatory Bowel Disease Paediatric Patients: A Prospective Study.
Moran-Lev Hadar,Galai Tut,Yerushalmy-Feler Anat,Weisman Yosef,Anafy Adi,Deutsch Varda,Cipok Michal,Lubetzky Ronit,Cohen Shlomi
Journal of Crohn's & colitis
BACKGROUND AND AIMS:The role of hepcidin in inflammatory bowel disease [IBD] in children with anaemia is poorly understood. However, it has been shown that vitamin D suppresses hepcidin expression. We aimed to assess serum hepcidin levels and the effect of vitamin D treatment on those levels in newly diagnosed IBD paediatric patients. METHODS:Eighty-five children were prospectively recruited in the Dana-Dwek Children's Hospital [40 newly diagnosed IBD, 45 healthy controls, 47% female, mean age 13.5 ± 3.4 years]. Blood samples for measurement of interleukin 6 [IL-6], C-reactive protein [CRP], hepcidin, iron parameters and 25-hydroxyvitamin D [25-(OH)-D] levels were obtained at baseline. Patients with mild-to-moderate signs and symptoms of IBD were treated with 4000 units of vitamin D daily for 2 weeks, after which the blood tests were repeated. RESULTS:Basal hepcidin, IL-6, CRP and platelet counts were significantly higher, and haemoglobin, serum iron and transferrin levels were significantly lower in the IBD children compared to controls [p < 0.001]. Eighteen patients completed 2 weeks of treatment with vitamin D. Following treatment, serum 25-(OH)-D concentrations increased by 40% [from 22.5 to 32.5 ng/mL], and serum hepcidin, CRP and ferritin levels decreased by 81%, 81% and 40% [from 33.9 to 6.7 ng/mL, from 23.9 to 4.7 mg/L, and from 27 to 16 ng/mL, respectively] [p ≤ 0.001]. CONCLUSION:Serum hepcidin levels were significantly higher in IBD paediatric patients compared to controls. Following vitamin D treatment, serum hepcidin concentration decreased significantly. These findings suggest a potential role for vitamin D in treating anaemia in IBD children. CLINICALTRIALS.GOV NUMBER:NCT03145896.
Retinoic acid modulates iron metabolism imbalance in anemia of inflammation induced by LPS via reversely regulating hepcidin and ferroportin expression.
Han Lu,Liu Yumei,Lu Meili,Wang Hongxing,Tang Futian
Biochemical and biophysical research communications
The present study was designed to investigate the effect of retinoic acid (RA) on anemia of inflammation (AI) induced by lipopolysaccharide (LPS) and explore the potential mechanisms. BALB/c mice were randomly assigned into four groups: control group; LPS (10 mg/kg) group, LPS + RA (3 mg/kg) and LPS + RA (15 mg/kg) groups. Red blood cell count (RBC), hemoglobulin (Hb), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin contentration (MCHC), erythropoietin (EPO) and iron content in both serum and liver tissue were measured. The AI model induced by LPS was successfully established represented by the decreases in RBC, Hb, HCT, MCV, MCHC and EPO for anemia indicators and by the increases in TNF-α, IL-18 and IL-1β contents for inflammation indicators. However, supplementation of RA increased the levels of anemia indicators and decreased the content of inflammation indicators. In addition, RA increased the content of iron in serum, while decreased its content in liver tissue. Furthermore, RA down-regulated the protein expression of hepcidin, toll-like receptor 4 (TLR4) and p-p65 in liver tissue, while up-regulated that of ferroportin. RA modulates iron metabolism imbalance in AI induced by LPS via reversely regulating hepcidin and ferroportin expression, which might be mediated by TLT-4/NFκB signaling pathway.
The opposing effects of acute inflammation and iron deficiency anemia on serum hepcidin and iron absorption in young women.
Stoffel Nicole U,Lazrak Meryem,Bellitir Souhaila,Mir Nissrine El,Hamdouchi Asmaa El,Barkat Amina,Zeder Christophe,Moretti Diego,Aguenaou Hassan,Zimmermann Michael B
Hepatic hepcidin synthesis is stimulated by inflammation but inhibited during iron deficiency anemia (IDA). In humans, the relative strength of these opposing signals on serum hepcidin and the net effect on iron absorption and systemic iron recycling is uncertain. In this prospective, 45-day study, in young women (n=46; age 18-49 years) with or without IDA, we compared iron and inflammation markers, serum hepcidin and erythrocyte iron incorporation from Fe-labeled test meals, before and 8, 24 and 36 hours (h) after influenza/DPT vaccination as an acute inflammatory stimulus. Compared to baseline, at 24-36 h after vaccination: 1) interleukin-6 increased 2-3-fold in both groups (<0.001); 2) serum hepcidin increased >2-fold in the non-anemic group (<0.001), but did not significantly change in the IDA group; 3) serum iron decreased in the non-anemic group (<0.05) but did not change in the IDA group; and 4) erythrocyte iron incorporation did not change in either of the two groups, but was approximately 2-fold higher in the IDA group both before and after vaccination (<0.001). In this study, mild acute inflammation did not increase serum hepcidin in women with IDA, suggesting low iron status and erythropoietic drive offset the inflammatory stimulus on hepcidin expression. In non-anemic women, inflammation increased serum hepcidin and produced mild hypoferremia, but did not reduce dietary iron absorption, suggesting iron-recycling macrophages are more sensitive than the enterocyte to high serum hepcidin during inflammation. The study was registered as a prospective observational trial at The study was funded by the International Atomic Energy Agency.
Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus.
Gardenghi Sara,Renaud Tom M,Meloni Alessandra,Casu Carla,Crielaard Bart J,Bystrom Laura M,Greenberg-Kushnir Noa,Sasu Barbra J,Cooke Keegan S,Rivella Stefano
Anemia of inflammation (AI) is commonly observed in chronic inflammatory states and may hinder patient recovery and survival. Induction of hepcidin, mediated by interleukin 6, leads to iron-restricted erythropoiesis and anemia. Several translational studies have been directed at neutralizing hepcidin overexpression as a therapeutic strategy against AI. However, additional hepcidin-independent mechanisms contribute to AI, which are likely mediated by a direct effect of inflammatory cytokines on erythropoiesis. In this study, we used wild-type, hepcidin knockout (Hamp-KO) and interleukin 6 knockout (IL-6-KO) mice as models of AI. AI was induced with heat-killed Brucella abortus (BA). The distinct roles of iron metabolism and inflammation triggered by interleukin 6 and hepcidin were investigated. BA-treated wild-type mice showed increased expression of hepcidin and inflammatory cytokines, as well as transitory suppression of erythropoiesis and shortened red blood cell lifespan, all of which contributed to the severe anemia of these mice. In contrast, BA-treated Hamp-KO or IL-6-KO mice showed milder anemia and faster recovery compared with normal mice. Moreover, they exhibited different patterns in the development and resolution of anemia, supporting the notion that interleukin 6 and hepcidin play distinct roles in modulating erythropoiesis in AI.
Vitamin D suppresses oxidative stress-induced microparticle release by human umbilical vein endothelial cells.
Jia Xiuyue,Xu Jie,Gu Yang,Gu Xin,Li Weimin,Wang Yuping
Biology of reproduction
Endothelial microparticle (MP) release was increased in numerous cardiovascular diseases including preeclampsia. Oxidative stress is a potent inducer of endothelial dysfunction. In this study, we aimed to investigate if vitamin D could protect endothelial cells (ECs) from MP release induced by oxidative stress. Endothelial cell (from human umbilical vein) oxidative stress was induced by cultivation of cells under lowered oxygen condition (2%O2) for 48 h and cells cultured under standard condition (21%O2) served as control. 1,25(OH)2D3 was used as bioactive vitamin D. Using annexin-V as a marker of released MP assessed by flow cytometry and cytochrome c reduction assay to measure EC superoxide generation, we found that MP release and superoxide generation were significantly increased when cells were cultured under 2%O2, which could be significantly inhibited by 1,25(OH)2D3. To study the potential mechanisms of 1,25(OH)2D3 protective effects on ECs, EC expression of endothelial nitric oxide synthase (eNOS), p-eNOSSer1177, p-eNOSThr495, caveolin-1, extracellular signal-regulated kinase (ERK), p-ERK, Akt, p-AktSer473, Rho-associated coiled-coil protein kinase 1 (ROCK1), and vitamin D receptor were determined. Microparticle expression of eNOS and caveolin-1 were also determined. We found that under lowered oxygen condition, 1,25(OH)2D3 could upregulate EC eNOS, p-eNOSSer1177, and p-AktSer473 expression, but inhibit cleaved ROCK1 expression. The upregulatory and inhibitory effects induced by 1,25(OH)2D3 were dose dependent. Strikingly, we also found that oxidative stress-induced decrease in ratio of eNOS and caveolin-1 expression in MP could be attenuated when 1,25(OH)2D3 was present in culture. These results suggest that upregulation of eNOSSer1177 and AktSer473 phosphorylation and inhibition of ROCK1 cleavage in EC and modulation of eNOS and caveolin-1 expression in MP could be plausible mechanisms of vitamin D protective effects on ECs.
Clinical implication of Frizzled 2 expression and its association with epithelial-to-mesenchymal transition in hepatocellular carcinoma.
Asano Tomonari,Yamada Suguru,Fuchs Bryan C,Takami Hideki,Hayashi Masamichi,Sugimoto Hiroyuki,Fujii Tsutomu,Tanabe Kenneth K,Kodera Yasuhiro
International journal of oncology
The epithelial-to-mesenchymal transition (EMT) is an initial, critical step in hepatocellular carcinoma (HCC) tumor invasion and metastasis. Frizzled 2 (Fzd2) expression might drive EMT through the non-canonical Wnt pathway, one of the various EMT signaling pathways. The expression of epithelial (E-cadherin) and mesenchymal (vimentin) markers, as well as that of Wnt5b, Stat3, IL-6, Jak2 and Fzd2, were measured in 15 HCC cell lines. The EMT status (vimentin to E-cadherin mRNA expression ratio), Fzd2 mRNA expression, and pSTAT3 protein expression were assessed by immunostaining in 100 HCC patients, and correlations of their expression with clinicopathological factors and prognosis were analyzed. Cell proliferation, migration, and invasiveness were assessed after Fzd2 knockdown. Fzd2 expression was significantly correlated with a mesenchymal phenotype in the HCC cell lines. Treatment of the cell lines with Fzd2 siRNA resulted in significantly reduced migration and invasiveness but did not affect proliferation. A significant correlation was detected between the EMT status and Fzd2 expression in the HCC patients. Multivariate analysis revealed that Fzd2 expression was an independent predictor of recurrence (P=0.034). Patients with high Fzd2 expression had significantly poorer recurrence‑free survival than those with low expression (P=0.03). Finally, pSTAT3 expression was significantly correlated with the EMT and Fzd2 status (P=0.0028, and P=0.0066, respectively). Fzd2 expression induced EMT and enhanced cell migration and invasiveness, and it might be a novel predictor of HCC recurrence. Furthermore, Stat3 might be controlled by both the Wnt5/Fzd2 and IL-6/Jak2 signaling pathways and play an important role in EMT.
Acidic Polysaccharide from Reverses Anemia of Chronic Disease Involving the Suppression of Inflammatory Hepcidin and NF-B Activation.
Wang Kaiping,Wu Jun,Cheng Fang,Huang Xiao,Zeng Fang,Zhang Yu
Oxidative medicine and cellular longevity
Anemia of chronic disease (ACD) is the second most prevalent anemia and frequently occurs in patients with acute or chronic immune activation. In the current study, we evaluated the therapeutic efficacy of polysaccharide (ASP) against ACD in rats and the potential mechanisms involved. The results showed that ASP inhibited inflammatory hepcidin in both HepG2 cells and ACD rats by blocking the IL-6/STAT3 and BMP/SMAD pathways. In ACD rats, the administration of ASP increased ferroportin expression, mobilized iron from the liver and spleen, increased serum iron levels, caused an elevation of serum EPO, and effectively relieved the anemia. Furthermore, ASP inhibited NF-B p65 activation via the IB kinases- (IKKs-) IB pathway, thereby reducing the secretion of interleukin-6 (IL-6) and TNF-, which is known to inhibit erythropoiesis. Our findings indicate that ASP is a potential treatment option for patients suffering from ACD.
Low Hemoglobin Level a Risk Factor for Acute Lower Respiratory Tract Infections (ALRTI) in Children.
Hussain Sheikh Quyoom,Ashraf Mohd,Wani Juveria Gull,Ahmed Javid
Journal of clinical and diagnostic research : JCDR
BACKGROUND:Acute lower respiratory tract infection is a major cause of death in under five years of age, and anemia is the commonest co-factor in pediatric patients seeking medical advice especially in developing countries. AIM:To analyze whether a low hemoglobin level is a risk factor for acute lower respiratory tract infections (ALRTI) in children. MATERIALS AND METHODS:Prospective case control study on 220 children (110 cases and controls each) was carried out in our children's hospital (G.B. Pant Hospital), an associated hospital of Government Medical College Srinagar, of Kashmir Northern India. All patients between the age of 1 month to 5 years of age who fulfilled the inclusion criteria were included. We used WHO criteria to diagnose ALRTI among the cases, and age and sex matched patients who did not have respiratory complaints were kept as controls. Patients who had congenital heart diseases, tuberculosis, malignancies, or dysmorphic features were excluded from the study. All patients were subjected to detailed history and through clinical examination followed by investigations like complete blood count (CBC), peripheral blood film (PBF) smear, blood culture and sensitivity test, X-ray chest, serum iron and iron binding capacity were done in all cases. RESULTS:Our study had slightly male preponderance 57.3% in study group and 59.1% in control group. Maximum number of children were between 3 months and 23 months both in the study (80.9%) as well as in the control (81.8%) group. In this study hemoglobin level <11 gm/dl was considered low. Mean Hb level was 8.8 gm/dl in the study group and 11.6 gm/dl in the control group. Anemia was found in 71 (64.5%) cases in the study group and in 31 (28.2%) cases in the control group. Anemic patients were found to be 4.6 times more susceptible to ALRTI in our study (Odds Ratio was 4.63), p-value <0.01. Iron deficiency was found in 78.9% of total anemic cases in the study group, p-value <0.01. In the study group, the mean serum iron level was 35.3 mcg/dl in the anemic cases and 57.1 mcg/dl in the non-anemic cases. while in the control group, these values were 52.4 mcg/dl and 62.6% mcg/dl respectively, (p-value ,<0.01). CONCLUSION:Anemia, predominantly iron deficiency anemia, was significantly found in ALTRI patients, and these patients were found to be 4.6 times more susceptible to ALRTI. Early and accurate diagnosis of anemia in children suffering from various ailments in particular to ALRTI will serve the mankind in a better way.
Implications of the Iron Deficiency in Lower Tract Respiratory Acute Infections in Toddlers.
Stepan D,Dop D,Moroşanu A,Vintilescu B,Niculescu C
Current health sciences journal
Iron deficiency anemia can result in an abnormal immune response and an increased incidence of the respiratory tract infections. In this study we analyzed statistically the association of acute lower respiratory tract infections with anemic status and associated risk factors for a number of 166 toddlers (1-3 years), using a control group of 26 cases without infectious status. The statistical analysis indicated the significant association of the infectious status with the anemic status of the patients as well as with the rural living areas, non-natural nutrition, prematurity and respiratory history. At the same time, we found a statistically significant association of anemic status with rural living areas and non-natural diet. The results obtained can be used to stratify patients for standardized treatment to regulate the iron metabolism and implicitly to combat the infectious disease.
The phenomenon of micronutrient deficiency among children in China: a systematic review of the literature.
Wong Angel Y S,Chan Esther W,Chui Celine S L,Sutcliffe Alastair G,Wong Ian C K
Public health nutrition
OBJECTIVE:The present study aimed to review the literature on micronutrient deficiency and other factors influencing a deficiency status among children living in China. DESIGN:A systematic review was performed to analyse the literature. SETTING:Studies were identified through a search of PubMed and secondary references. SUBJECTS:Children living in China aged less than 18 years. RESULTS:Sixty-one articles were included. The prevalence of vitamin A deficiency decreased to approximately 10 % in 1995-2009. It increased with age but no significant difference was found between genders. The prevalence of thiamin and vitamin B12 deficiency was 10·5 % in Yunnan and 4·5 % in Chongqing provinces, respectively. Higher vitamin D deficiency rates were seen in spring and winter. The incidence of bleeding due to vitamin K deficiency was 3·3 % in 1998-2001 and more prevalent in rural areas. Both iodine deficiency and excess iodine intake were observed. Goitre rates were reported in Tibet, Jiangxi, Gansu and Hong Kong (3·5-46 %). Anaemia rates ranged from 20 % to 40 % in 2007-2011. High Se deficiency rates were found in Tibet, Shaanxi and Jiangsu. High Zn deficiency rates were also found (50-70 %) in 1995-2006. Few studies reported Ca deficiency rates (19·6-34·3 %). The degrees of deficiency for vitamin A, vitamin B12, Fe and Zn were more substantial in rural areas compared with urban areas. CONCLUSIONS:The prevalence of micronutrient deficiency rates varied. Socio-economic status, environmental factors and the Chinese diet may influence micronutrient deficiency. Public health policies should consider implementing programmes of supplementation, food fortification and nutrition education to address these deficiencies among Chinese children.
Vitamin and Mineral Supplementation During Pregnancy on Maternal, Birth, Child Health and Development Outcomes in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis.
Oh Christina,Keats Emily C,Bhutta Zulfiqar A
Almost two billion people are deficient in key vitamins and minerals, mostly women and children in low- and middle-income countries (LMICs). Deficiencies worsen during pregnancy due to increased energy and nutritional demands, causing adverse outcomes in mother and child, but could be mitigated by interventions like micronutrient supplementation. To our knowledge, this is the first systematic review that aimed to compile evidence from both efficacy and effectiveness trials, evaluating different supplementation interventions on maternal, birth, child health, and developmental outcomes. We evaluated randomized controlled trials and quasi-experimental studies published since 1995 in peer-reviewed and grey literature that assessed the effects of calcium, vitamin A, iron, vitamin D, and zinc supplementation compared to placebo/no treatment; iron-folic (IFA) supplementation compared to folic acid only; multiple micronutrient (MMN) supplementation compared to IFA; and lipid-based nutrient supplementation (LNS) compared to MMN supplementation. Seventy-two studies, which collectively involved 314 papers (451,723 women), were included. Meta-analyses showed improvement in several key birth outcomes, such as preterm birth, small-for-gestational age (SGA) and low birthweight with MMN supplementation, compared to IFA. MMN also improved child outcomes, including diarrhea incidence and retinol concentration, which are findings not previously reported. Across all comparisons, micronutrient supplementation had little to no effect on mortality (maternal, neonatal, perinatal, and infant) outcomes, which is consistent with other systematic reviews. IFA supplementation showed notable improvement in maternal anemia and the reduction in low birthweight, whereas LNS supplementation had no apparent effect on outcomes; further research that compares LNS and MMN supplementation could help understand differences with these commodities. For single micronutrient supplementation, improvements were noted in only a few outcomes, mainly pre-eclampsia/eclampsia (calcium), maternal anemia (iron), preterm births (vitamin D), and maternal serum zinc concentration (zinc). These findings highlight that micronutrient-specific supplementation should be tailored to specific groups or needs for maximum benefit. In addition, they further contribute to the ongoing discourse of choosing antenatal MMN over IFA as the standard of care in LMICs.
Effect of vitamin A, calcium and vitamin D fortification and supplementation on nutritional status of women: an overview of systematic reviews.
Rajwar Eti,Parsekar Shradha S,Venkatesh Bhumika Tumkur,Sharma Zinnia
BACKGROUND:Micronutrient deficiency affects the health and development of vulnerable population such as children and pregnant women. Measures such as fortification of food and supplementation have been implemented to prevent or control deficiencies related to micronutrients. OBJECTIVE:To assess the effect of vitamin A, vitamin D, and calcium fortification and supplementation on nutritional status of women in reproductive age group. To assess the toxicities and adverse events related to intervention. METHODOLOGY:Systematic reviews including RCTs on women of reproductive age group provided with vitamin A, vitamin D, and calcium supplementation or fortified food were included, to report all malnutrition-related outcomes due to deficiency of the abovementioned micronutrients. The Cochrane Database of Systematic Reviews, EPPI Centre, Campbell Collaboration, PubMed, Web of Science, and Scopus were searched electronically for English language publications, until 31 March 2018. Hand searching of the articles was done from the Journal of Food Science and Technology. Two independent reviewers selected the systematic reviews, extracted data, and assessed for the quality. RESULTS:A total of 16 systematic reviews were included in narrative synthesis. Supplementation of vitamin A was reported to result in increased maternal serum retinol concentrations and increased breast milk retinol concentration. It reduced the risk of anemia (Hb < 11 g/dL) and reduced maternal clinical infection. Vitamin D supplementation increased 25-hydroxy vitamin D levels. There was insufficient evidence for the effect on bone mineral density and serum calcium levels. Calcium supplementation did not have any significant effect on body weight, weight gain, and body mass index of the participants. CONCLUSION:This overview of systematic reviews reiterates the nutritional importance of vitamin A, vitamin D, and calcium supplementation for the reproductive age women. However, there was no empirical evidence available for fortification of food with vitamin A, vitamin D, and calcium and nutritional benefits of the same for reproductive age women, therefore thrusting upon the need of conducting future quality research, i.e., clinical trials and systematic reviews for food fortification. SYSTEMATIC REVIEW REGISTRATION:A priori protocol for this overview of systematic reviews was registered in PROSPERO with registration number CRD42018089403 .
Factors associated with childhood anaemia in Afro-descendant communities in Alagoas, Brazil.
Ferreira Haroldo da Silva,Santos Laíse Gabrielly Matias de Lima,Ferreira Carla Mariana Xavier,Kassar Samir Buainain,Dos Santos Tamara Rodrigues,Vasconcelos Nancy Borges Rodrigues,de Assunção Monica Lopes,Cardoso Marly Augusto
Public health nutrition
OBJECTIVE:To investigate factors associated with anaemia in preschool children. DESIGN:A home survey was conducted in 2018. Anaemia in children (capillary blood Hb level < 110 g/l) was the outcome, and socio-economic, demographic and health factors of the mother and child were the independent variables. The measure of association was the prevalence ratio, and its 95 % CI was calculated using Poisson's regression with robust variance and hierarchical selection of independent variables. SETTING:Afro-descendants communities living in the state of Alagoas, northeast Brazil. PARTICIPANTS:Children aged 6-59 months and their mothers (n 428 pairs). RESULTS:The prevalence of child anaemia was 38·1 % (95 % CI 33·5, 42·7). The associated factors with child anaemia were male sex, age < 24 months, larger number of residents at home (> 4), relatively taller mothers (highest tertile) and higher z-score of BMI for age, after further adjustment for wealth index, vitamin A supplementation in the past 6 months and clinical visit in the last 30 d. CONCLUSIONS:The high prevalence of anaemia observed reveals a relevant public health problem amongst children under five from the quilombola communities of Alagoas. Considering the damage caused to health and multiplicity of risk factors associated with anaemia, the adoption of intersectoral strategies that act on modifiable risk factors and increase vigilance concerning those that are not modifiable becomes urgent.
Risk factors for vitamin A and vitamin D deficiencies in children younger than 5 years in the occupied Palestinian territory: a cross-sectional study.
Chaudhry Aeysha,Hajat Shakoor,Rizkallah Najwa,Abu-Rub Ala'a
Lancet (London, England)
BACKGROUND:Vitamin A and vitamin D are essential for a child's growth and development. However, research on micronutrients in the occupied Palestinian territory is scarce. The aim of this study was to ascertain the prevalence and risk factors of vitamin A and vitamin D deficiencies in children living in the occupied Palestinian territory. METHODS:The Palestinian Micronutrient Survey in 2013 measured concentrations of vitamin A in 1054 children (569 children in the West Bank and 485 children in the Gaza Strip) and vitamin D in 150 children (75 children in the West Bank and 75 children in the Gaza Strip). Risk factors for deficiency were assessed in children aged 6-59 months using χ tests and logistic regression with each of the outcome variables of vitamin A and vitamin D deficiencies. A child was considered deficient if serum concentrations were less than 1·05 μmol/L vitamin A or less than 50 nmol/L vitamin D. Multiple logistic regression models were developed to identify independent risk factors. Ethical approval was obtained from the London School of Hygiene & Tropical Medicine. FINDINGS:771 (73%) children in the survey had vitamin A deficiency, and 91 (61%) children had vitamin D deficiency. Compared with children living in the West Bank, children living in the Gaza Strip were more likely to be deficient in vitamin A (odds ratio 1·34, 95% CI 0·78-2·31) and vitamin D (1·96, 0·67-5·71). Vitamin A deficiency was 1·5 more likely in children with anaemia than in children who did not have anaemia (95% CI 1·08-2·10; p=0·047). Vitamin D deficiency was more common in children older than 1 years than in children aged 1 year or younger, and vitamin D deficiency was 2·72 times more likely in girls than in boys (95% CI 1·21-6·01; p=0·037). INTERPRETATION:The study provides an initial assessment of the burden of vitamin A and vitamin D deficiencies in the occupied Palestinian territory. However, due to the small sample size, more robust research is needed. The observed low adherence to the full supplementation regimen warrants further research into methods of effective service delivery by health service providers. FUNDING:None.
Magnitude and factors associated with upper respiratory tract infection among under-five children in public health institutions of Aksum town, Tigray, Northern Ethiopia: an institutional based cross-sectional study.
Zeru Teklay,Berihu Hagos,Buruh Gerezgiher,Gebrehiwot Haftom
The Pan African medical journal
Introduction:upper respiratory tract infection is a leading cause of morbidity among under-five, particularly in the developing countries. Delays in the identification and treatment of under-fives are among the main contributors to the complication. The aim of this study was to assess the magnitude and to identify factors associated with upper respiratory tract infection among under-five children, in public health institutions of Aksum City, Tigray Region, North Ethiopia, 2016. Methods:institutional based cross-sectional study was done. Cases were under-five children who had get service. The study participants were selected using Systematic random sampling technique. Data were entered, using Epi-info version 7 and analyzed using SPSS version 22.0. Clinical data from the chart were used to diagnose upper respiratory tract infection types. The binary logistic regression model was used to test the association between dependent and independent variables and multivariable logistic regression was used to identify the associated factors to upper respiratory tract infections. Results:out of 213 study participants 52.6% identified as having at least one type of upper respiratory tract infection, i.e. sinusitis 22 (10.3%), 37 (17.4%) otitis media, 39 (18.3%) tonsillitis and common cold 83 (39.0%). Multivariable logistic regression analysis shows that rural residence 7.6 [AOR (95%CI) (2.49, 23.58)], civil servant father's children 4.49 [AOR (95%CI) (1.57, 12.83)], non-immunization 6.0 [AOR(95%CI) (1.38, 26.8)], mud house wall 4.58 [AOR (95%CI) (1.74, 12.0)], rental house 5.1 [AOC (95% CI) (1.82, 14.6] and large family size 5.3 [AOC (95%CI) (2.3, 12.1 )], were found to be statistically associated. Conclusion:socioeconomic, maternal and environmental factors had contributed to the upper respiratory tract infection. Strengthening of the existing disease prevention policy as well as improvement of institutional health service behavior is crucial.
The immunomodulatory effects of vitamin D drops in children with recurrent respiratory tract infections.
Xiao Jianqiu,He Wei
American journal of translational research
OBJECTIVE:To investigate the effects of vitamin D drops on immune function in children with recurrent respiratory tract infections (RRTI). METHODS:The clinical data of 119 children with RRTI in our hospital were retrospectively retrieved, and they were divided into group A (n=59, receiving routine treatment) and group B (n=60, receiving vitamin D drops) based on their treatment modality. The clinical efficacy, symptom disappearance time, immune function index, insulin-like growth factor (IGF-1), 25-hydroxyvitamin D [25-(OH)D], serum y-interferon (INF-y), and the number of episodes of respiratory tract infections were compared between the two groups. RESULTS:The total effective rate of treatment in group B was 96.67%, which was significantly higher than 71.19% in group A (<0.05). Children in group B had shorter time to disappearance of lung rales, cough, and fever than group A (<0.05). Group B had higher IgA, IgG, and IgM levels, higher CD4, CD3 levels and lower CD8 levels as well as higher IGF-1, 25-(OH)D, INF-y levels, and fewer respiratory infections after treatment than group A (<0.05). CONCLUSION:Vitamin D drops are effective in the treatment of children with RRTI, which is beneficial to the improvement of clinical symptoms and immune function.
Children with lower respiratory tract infections and serum 25-hydroxyvitamin D levels: A case-control study.
Velarde López Angel Alfonso,Gerber Jeffrey S,Leonard Mary B,Xie Dawei,Schinnar Rita,Strom Brian L
BACKGROUND:Pneumonia is the leading cause of death in children under age of 5 years worldwide. The role of vitamin D in respiratory infections including pneumonia is unclear; therefore, we aimed to determine if children with lower respiratory tract infections had low serum 25-hydroxyvitamin D . METHODS:We performed a case-control study of children ages 3-60 months from the Guatemala City metropolitan area, hospitalized with community-acquired pneumonia between September and December 2012. Controls were selected from the well-baby/care immunization clinics serving the population from which cases emerged. We analyzed serum 25-hydroxyvitamin D levels and conducted parental interviews to assess subject age, sex, race, feeding type, vitamin D supplementation, frequency of sun exposure, and maternal education. Height and weight were ascertained from medical records. Complete information was available for 70 (83%) of 84 eligible cases and 68 (60%) of 113 eligible controls. RESULTS:The median (IQR) serum 25-hydroxyvitamin D concentration for cases was 23.2 ng/ml (14.4-29.9) compared to 27.5 ng/ml (21.4-32.3) in controls (P = 0.006). Multiple regression analysis using an a priori cut-point for vitamin D of <20 ng/ml showed that children with lower respiratory tract infections were more likely to have low 25-hydroxyvitamin D levels than controls (adjusted odds ratio 2.4, 95% confidence interval 1.1-5.2, P = 0.02). CONCLUSIONS:Children with lower respiratory tract infections in Guatemala had low 25-hydroxyvitamin D levels. Pediatr Pulmonol. 2016;51:1080-1087. © 2016 Wiley Periodicals, Inc.
Serum vitamin D concentrations and associated severity of acute lower respiratory tract infections in Japanese hospitalized children.
Inamo Yasuji,Hasegawa Maki,Saito Katsuya,Hayashi Rika,Ishikawa Teruaki,Yoshino Yayoi,Hashimoto Koji,Fuchigami Tatsuo
Pediatrics international : official journal of the Japan Pediatric Society
BACKGROUND:Vitamin D is an immunomodulatory molecule related to innate immunity that may contribute to the increased occurrence of acute lower respiratory infection (ALRI) in children, one of the most common reasons for hospitalization and intensive care unit admission. In the present study, the association between vitamin D deficiency and the severity of respiratory infection was evaluated by determining serum concentrations of 25-hydroxyvitamin D (25(OH)D) in a group of hospitalized children with ALRI. METHODS:Of the 28 children admitted to Nihon University Nerima-Hikarigaoka Hospital with ALRI over the period November 2008–May 2009, 26 were diagnosed as having bronchiolitis and two were found to have pneumonia. A competitive protein binding radioimmunoassay was used to determine serum 25(OH)D concentrations. RESULTS:Mean 25(OH)D concentrations in breast-fed children with ALRI (n = 7) were significantly lower than those in children with ALRI who were bottle fed/weaned (n = 6) or on a regular diet (n = 15; 14.6 ± 9.7, 28.9 ± 6.9 and 24.6 ± 8.8 ng/mL, respectively). There was a significant correlation between vitamin D deficiency (<15 ng/mL) and the need for supplementary oxygen and ventilator management. CONCLUSION:Significantly more children with ALRI who needed supplementary oxygen and ventilator management were vitamin D deficient. These findings suggest that the immunomodulatory properties of vitamin D may influence the severity of ALRI.
Low serum 25-hydroxyvitamin D level and risk of upper respiratory tract infection in children and adolescents.
Science Michelle,Maguire Jonathon L,Russell Margaret L,Smieja Marek,Walter Stephen D,Loeb Mark
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
BACKGROUND:Vitamin D may be important for immune function. Studies to date have shown an inconsistent association between vitamin D and infection with respiratory viruses. The purpose of this study was to determine if serum 25-hydroxyvitamin D (25(OH)D) was associated with laboratory-confirmed viral respiratory tract infections (RTIs) in children. METHODS:Serum 25(OH)D levels were measured at baseline and children from Canadian Hutterite communities were followed prospectively during the respiratory virus season. Nasopharyngeal specimens were obtained if symptoms developed and infections were confirmed using polymerase chain reaction. The association between serum 25(OH)D and time to laboratory-confirmed viral RTI was evaluated using a Cox proportional hazards model. RESULTS:Seven hundred forty-three children aged 3-15 years were followed between 22 December 2008 and 23 June 2009. The median serum 25(OH)D level was 62.0 nmol/L (interquartile range, 51.0-74.0). A total of 229 participants (31%) developed at least 1 laboratory-confirmed viral RTI. Younger age and lower serum 25(OH)D levels were associated with increased risk of viral RTI. Serum 25(OH)D levels <75 nmol/L increased the risk of viral RTI by 50% (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.10-2.07, P = .011) and levels <50 nmol/L increased the risk by 70% (HR, 1.67; 95% CI, 1.16-2.40, P = .006). CONCLUSIONS:Lower serum 25(OH)D levels were associated with increased risk of laboratory-confirmed viral RTI in children from Canadian Hutterite communities. Interventional studies evaluating the role of vitamin D supplementation to reduce the burden of viral RTIs are warranted.
Vitamin D status and hospitalisation for childhood acute lower respiratory tract infections in Nigeria.
Ahmed Patience,Babaniyi I B,Yusuf K K,Dodd Caitlin,Langdon Gretchen,Steinhoff Mark,Dawodu Adekunle
Paediatrics and international child health
BACKGROUND:Acute lower respiratory tract infection (ALRTI) is the leading cause of childhood deaths in most developing countries, including Nigeria. Vitamin D is associated with innate immunity and may play a role in the control of infections. Case-control studies, including a small study from Nigeria, show inconsistent results for the association between vitamin D status and risk of ALRTI. AIMS:To examine the relationship between vitamin D status and hospitalization for ALRTI in Nigerian children. METHODS:Fifty children aged 2-60 months hospitalised with ALRTI were studied prospectively. ALRTI was diagnosed on the basis of modified WHO criteria. Each patient was matched with controls for age and gender. The controls were enrolled either from children attending well-child clinics or general clinics without evidence of respiratory infection or admitted to the hospital for elective surgery. A structured questionnaire collected data on demography, health, diet, duration of exposure to sunlight and percentage of body surface exposed to sunlight (according to type of clothing) while outdoors, and potential risk factors for ALRTI. Serum 25-hydroxyvitamin D [25(OH)D] concentration was measured using a chemiluminescenceimmuno-assay. The differences between cases and controls in serum 25(OH)D concentrations, association between vitamin D status and ALRTI and risk factors for vitamin D deficiency were assessed. RESULTS:Mean (SD) 25(OH)D concentrations in patients and controls were similar [61·5 (25·8) vs 63·1 (22·9) nmol/L,P = 0·95].25% of all 100 subjects studied had serum 25(OH)D<50 nmol/L. In a multiple conditional logistic regression model, only lower percentage of body surface area exposed to sunlight was associated with increased risk of ALRTI. The percentage of body surface area exposed to sunlight while outdoors (P = 0·028) and vitamin D supplement use (P = 0·009) were independent determinants of vitamin D deficiency in the overall study population. CONCLUSIONS:ALRTI was not associated with vitamin D status, but was associated with less exposure to sunlight. Exposure to sunlight and vitamin D supplementation contributed to vitamin D status in this population.
Vitamin D status and vitamin D receptor gene polymorphism in Saudi children with acute lower respiratory tract infection.
Mansy Wael,Ibrahim Nermin H,Al-Gawhary Somaya,Alsubaie Sarah S,Abouelkheir Manal M,Fatani Amal,Abd Al Reheem Fadwa,El Awady Heba,Zakaria Enas A
Molecular biology reports
There is a significant association exists between vitamin D deficiencies, low respiratory tract infections, and certain types of VDR gene polymorphism. Various studies are being conducted to prove any such link between the different clinical conditions due to disturbed vitamin D regulation and VDR gene polymorphisms. The present study analyzed the presence of vitamin D receptor (VDR) gene polymorphisms (ApaI and TaqI) in Saudi pediatric patient suffering from acute lower respiratory tract infection (ALRTI) cases. Fifty children (50) with ALRTI admitted at King Saud University Medical City, Riyadh/Saudi Arabia were included in addition to seventy-three (73) apparently healthy children who were considered as the control group. Genomic DNA from whole blood was extracted and subjected to polymerase chain reaction (PCR) targeting TaqI and ApaI VDR polymorphisms. RFLP-PCR genotyping was performed to determine the allelic frequency within the VDR gene. In the whole sample, the allelic frequency of ApaI polymorphism in the VDR gene was 58.5%, 17.9%, and 23.6% for AA, Aa, and aa respectively (p = 0.11), while it was 48%, 19%, and 33% for TT, Tt, and tt respectively (p = 0.33) with regards to the frequency of TaqI polymorphism in the VDR gene. VDR ApaI Aa and aa genotypes and VDR TaqI Tt and tt genotypes were not associated with increased risk of ALRTI in children (OR 0.87, 95% CI 0.33-2.28, p = 0.77; OR 0.56, 95% CI 0.23-1.4, p = 0.21; OR 1.15, 95% CI 0.44-2.99, p = 0.77; OR 0.73, 95% CI 0.32-1.68, p = 0.46 respectively). To conclude, neither vitamin D status nor VDR gene polymorphisms such as ApaI and TaqI is associated with increased susceptibility to ALRTI. Linkage disequilibrium was not detected between ApaI and TaqI VDR gene polymorphisms as in the case of serum vitamin D status in ALRTI patients versus apparent healthy children.
Mechanisms of Action of Vitamin D as Supplemental Therapy for Pneumocystis Pneumonia.
Lei Guang-Sheng,Zhang Chen,Cheng Bi-Hua,Lee Chao-Hung
Antimicrobial agents and chemotherapy
The combination of trimethoprim and sulfamethoxazole (TMP-SMX) is the most effective regimen for therapy of pneumonia (PCP). As many patients with PCP are allergic or do not respond to it, efforts have been devoted to develop alternative therapies for PCP. We have found that the combination of vitamin D (VitD3) (300 IU/kg/day) and primaquine (PMQ) (5 mg/kg/day) was as effective as TMP-SMX for therapy of PCP. In this study, we investigated the mechanisms by which vitamin D enhances the efficacy of PMQ. C57BL/6 mice were immunosuppressed by CD4 cell depletion, infected with for 8 weeks, and then treated for 9 days with the combination of VitD3 and PMQ (VitD3-PMQ) or with TMP-SMX or PMQ to serve as controls. The results showed that vitamin D supplementation increased the number of CD11c cells, suppressed the production of proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], gamma interferon [IFN-γ], and interleukin-6 [IL-6]) and inducible nitric oxide synthase (iNOS), and enhanced the expression of genes related to antioxidation (glutathione reductase and glutamate-cysteine ligase modifier subunit), antimicrobial peptides (cathelicidin), and autophagy (ATG5 and beclin-1). These results suggest that the main action of vitamin D is enhancing the ability of the host to defend against infection.
The associations of economic growth and anaemia for school-aged children in China.
Luo Dongmei,Xu Rongbin,Ma Jun,Yan Xiaojin,Hu Peijin,Song Yi,Jan Catherine,Raat Hein,Patton George C
Maternal & child nutrition
Economic growth has brought improvements in many areas of child health, but its effects on anaemia among school-aged children remain unknown. However, this is important because iron deficiency anaemia is common and is the main cause of disability-adjusted life years for school-aged children. In this study, we included 429,222 Chinese children aged 7-17 years from five consecutive national cross-sectional surveys during 1995-2014. Using altitude-adjusted haemoglobin concentration measured from capillary blood samples, we defined anaemia status according to World Health Organization's recommendation. We used logistic regressions weighted by provincial population to examine the association between provincial gross domestic product (GDP) per capita and anaemia, adjusting for sex, age, urban-rural location, regional socio-economic status (SES), fixed effect of province, and clustering of schools. We used generalised additive mixed models to evaluate a potentially non-linear relationship. For each 100% growth in GDP per capita, there was a 40% (odds ratio [OR] = 0.60; 95% confidence interval [CI; 0.56, 0.65]) reduction in anaemia. However, the association was weaker for girls and in cities with a lower SES. The association was weaker across 2005-2014 (OR = 0.75, 95% CI [0.62, 0.90]) compared with 1995-2005 (OR = 0.52; 95% CI [0.44, 0.61]), reflecting a weaker association when GDP per capita reaches around $2,000. The results were similar for moderate-to-severe anaemia. We concluded that economic growth has been associated with reductions in anaemia among school-aged children in China but with fewer benefits for girls and those in poorer settings. Further economic development in China is unlikely to bring similar reductions in anaemia, suggesting that additional population level and targeted interventions will be needed.
Association between Anaemia in Children 6 to 23 Months Old and Child, Mother, Household and Feeding Indicators.
Prieto-Patron Alberto,Van der Horst Klazine,Hutton Zsuzsa V,Detzel Patrick
In Low and Lower-Middle-Income countries, the prevalence of anaemia in infancy remains high. In early childhood anaemia cause irreversible cognitive deficits and represents a higher risk of child mortality. The consequences of anaemia in infancy are a major barrier to overcome poverty traps. The aim of this study was to analyse, based on a multi-level approach, different factors associated with anaemia in children 6⁻23 months old based on recent available Standard Demographic Health Surveys (S-DHS). We identified 52 S-DHS that had complete information in all covariates of interest in our analysis between 2005 and 2015. We performed traditional logistic regressions and multilevel logistic regression analyses to study the association between haemoglobin concentrations and household, child, maternal, socio-demographic variables. In our sample, 70% of the 6⁻23 months-old children were anaemic. Child anaemia was strongly associated with maternal anaemia, household wealth, maternal education and low birth weight. Children fed with fortified foods, potatoes and other tubers had significantly lower rates of anaemia. Improving overall household living conditions, increasing maternal education, delaying childbearing and introducing iron rich foods at six months of age may reduce the likelihood of anaemia in toddlerhood.
Characterisation of the types of anaemia prevalent among children and adolescents aged 1-19 years in India: a population-based study.
Sarna Avina,Porwal Akash,Ramesh Sowmya,Agrawal Praween K,Acharya Rajib,Johnston Robert,Khan Nizamuddin,Sachdev H P S,Nair K Madhavan,Ramakrishnan Lakshmy,Abraham Ransi,Deb Sila,Khera Ajay,Saxena Renu
The Lancet. Child & adolescent health
BACKGROUND:Anaemia is a serious public health concern in India. However, national estimates for its prevalence are not available for the 5-14 years age group, nor are estimates available for the types of anaemia among children and adolescents (1-19 years). We aimed to assess the prevalence of anaemia among children and adolescents in India and to categorise types of anaemia on the basis of micronutrient deficiencies. METHODS:We assessed the prevalence of anaemia among children (1-4 years and 5-9 years) and adolescents (10-19 years) using nationally representative data from the Comprehensive National Nutrition Survey. Anaemia was classified on the basis of age and sex-specific WHO cutoffs and serum ferritin, soluble transferrin receptor, folate, cyanocobalamin, and C-reactive protein concentrations as iron deficiency anaemia, folate or vitamin B12 deficiency anaemia, dimorphic anaemia (iron deficiency anaemia and folate or vitamin B12 deficiency anaemia), anaemia of other causes (anaemia not classified as iron deficiency anaemia and folate or vitamin B12 deficiency anaemia), and anaemia of inflammation. FINDINGS:We included 26 765 children (11 624 aged 1-4 years and 15 141 aged 5-9 years) and 14 669 adolescents. In the weighted sample, anaemia prevalence was 40·5% (4553 of 11 233) among 1-4 year-olds, 23·4% (3439 of 14 664) among 5-9 year-olds, and 28·4% (4064 of 14 300) among adolescents. Among 2862 children aged 1-4 years, iron deficiency anaemia (1045 [36·5%]) was the most prevalent type, followed by anaemia of other causes (702 [24·5%]), folate or vitamin B12 deficiency anaemia (542 [18·9%]), dimorphic anaemia (387 [13·5%]), and anaemia of inflammation (186 [6·5%]). Among 2261 children aged 5-9 years, anaemia of other causes was the most common (986 [43·6%]), followed by folate or vitamin B12 deficiency anaemia (558 [24·6%]), iron deficiency anaemia (353 [15·6%]), dimorphic anaemia (242 [10·7%]), and anaemia of inflammation (122 [5·4%]). 861 (31·4%) of 2740 adolescents had anaemia of other causes, 703 (25·6%) had folate or vitamin B12 deficiency anaemia, 584 (21·3%) had iron deficiency anaemia, 498 (18·2%) and dimorphic anaemia, and 94 (3·4%) had anaemia of inflammation. INTERPRETATION:Iron deficiency anaemia is the most common form of anaemia among younger children and anaemia of other causes among 5-9-year-old children and adolescents. Folate or vitamin B12 deficiency anaemia accounts for more than a third of anaemia prevalence. Anaemia prevention efforts should focus on strengthening the existing iron and folate supplementation programmes and prevention of folate or vitamin B12 deficiency anaemia. FUNDING:The Mittal Foundation.
Anaemia and Its Relation to Demographic, Socio-economic and Anthropometric Factors in Rural Primary School Children in Hai Phong City, Vietnam.
Hoang Ngan T D,Orellana Liliana,Le Tuyen D,Gibson Rosalind S,Worsley Anthony,Sinclair Andrew J,Hoang Nghien T T,Szymlek-Gay Ewa A
Little is known about the prevalence of anaemia and associated factors in school children in Vietnam. In this cross-sectional study, we aimed to determine the prevalence of anaemia and its subtypes, and the associations of types of anaemia with demographic, socio-economic and anthropometric factors among 6-9-year-old primary school children in rural areas of Hai Phong City, Vietnam. Haemoglobin (Hb) and mean corpuscular volume (MCV) were measured, and demographic, socio-economic and anthropometric data were collected in 893 children from eight primary schools. The prevalence of anaemia (Hb < 115 g/L) was 12.9% (95% CI: 8.1%, 19.9%), microcytic anaemia (Hb < 115 g/L and MCV < 80 fL) was 7.9% (95% CI: 5.3%, 11.6%) and normocytic anaemia (Hb < 115 g/L and MCV 80-90 fL) was 5.3% (95% CI: 2.9%, 9.5%). No child presented with macrocytic anaemia (Hb < 115 g/L and MCV > 90 fL). Children who were underweight, wasted, or in anthropometric failure (either underweight, stunted or wasted) were more likely to be anaemic (all ≤ 0.004), and specifically, to have normocytic anaemia (all ≤ 0.006), than those who were not underweight, wasted or in anthropometric failure. Stunted children were more likely to be anaemic ( = 0.018) than those who were not stunted. Overweight/obese children were less likely to be anaemic ( = 0.026) or have normocytic anaemia ( = 0.038) compared with children who were not overweight/obese. No anthropometric status indicator was associated with the risk of microcytic anaemia. No demographic or socio-economic factor was associated with any type of anaemia. Anaemia remains a public health issue in rural areas in Hai Phong City, Vietnam, and future approaches for its prevention and control should target undernourished primary school children.
[Risk factors for nutritional iron deficiency anemia in children].
Lei Qing-Ling,Dai Bi-Tao,Xian Ying,Yu Jie
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics
OBJECTIVE:To investigate the clinical features of nutritional iron deficiency anemia (IDA) and analyze the risk factors for the severity of anemia, and to provide a basis for the prevention and clinical diagnosis and treatment of this disease. METHODS:A retrospective analysis was performed on the clinical data of 372 children with IDA to investigate the risk factors for the severity of IDA. RESULTS:Of 372 cases, the male-to-female ratio of these patients was 2.72 : 1. Of all cases, 79.9% were aged 6 months to 2 years, and 30.7% were premature infants; 22.9% had a birth weight of < 2.5 kg, and 77.1% had a birth weight of ≥2.5 kg; 36.0% were delivered by natural birth, and 64.0% were delivered by caesarean section; 79.3% were not given solid foods in time; 46.2% had a history of lower respiratory tract infection/recurrent upper respiratory tract infection, diarrhea, trauma, or surgery. The univariate analysis showed that age, birth weight, gestational age, timely introduction of solid foods, and a history of lower respiratory tract infection/recurrent upper respiratory tract infection, diarrhea, trauma, or surgery were associated with the severity of anemia. The multivariate analysis showed that birth weight and the mentioned medical history were associated with the severity of anemia. CONCLUSIONS:Nutritional IDA is common in children aged 6 months to 2 years. Nowadays, improper feeding pattern is still one of the main causes of IDA. Birth weight and a history of lower respiratory tract infection/recurrent upper respiratory tract infection, diarrhea, trauma, or surgery are closely associated with the severity of anemia.
Factors associated with mortality in children under five years old hospitalized for Severe Acute Malnutrition in Limpopo province, South Africa, 2014-2018: A cross-sectional analytic study.
Gavhi Fhatuwani,Kuonza Lazarus,Musekiwa Alfred,Motaze Nkengafac Villyen
BACKGROUND:In South Africa, 30.9% of children under five years with Severe Acute Malnutrition (SAM) died in 2018. We aimed to identify factors associated with mortality among children under five years hospitalized with SAM in Limpopo province, South Africa. METHODS:We conducted a cross-sectional study including children under five years admitted with SAM from 2014 to 2018 in public hospitals of Limpopo province. We extracted socio-demographic and clinical data from hospital records. We used logistic regression to identify factors associated with mortality. FINDINGS:We included 956 children, 50.2% (480/956) male and 49.8% (476/956) female. The median age was 13 months (inter quartile range: 9-19 months). The overall SAM mortality over the study period was 25.9% (248/956). The most common complications were diarrhea, 63.8% (610/956), and lower respiratory tract infections (LRTIs), 42.4% (405/956). Factors associated with mortality included herbal medication use (adjusted Odds Ratio (aOR): 2.2, 95% Confidence Interval (CI): 1.4-3.5, p = 0.001), poor appetite (aOR: 2.7, 95% CI: 1.4-5.2, p = 0.003), Mid-upper circumference (MUAC) <11.5 cm (aOR: 3.0, 95% CI: 1.9-4.7, p<0.001), lower respiratory tract infections (LRTIs) (aOR: 1.6, 95% CI: 1.2-2.0, p<0.001), anemia (aOR: 2.5, 95% CI: 1.1-5.3, p = 0.021), hypoglycemia (aOR: 12.4, 95% CI: 7.1-21.8, p<0.001) and human immunodeficiency virus (HIV) infection (aOR: 2.3, 95% CI: 1.6-3.3, p<0.001). INTERPRETATION:Herbal medication use, poor appetite, LRTIs, anemia, hypoglycemia, and HIV infection were associated with mortality among children with SAM. These factors should guide management of children with SAM.
Childhood iron deficiency anemia leads to recurrent respiratory tract infections and gastroenteritis.
Jayaweera Jayaweera Arachchige Asela Sampath,Reyes Mohammed,Joseph Anpalaham
Anemia affects approximately 30% of children all over the world. Acute respiratory tract infections (ARTI), urinary tract infections (UTI) and gastroenteritis (GE) are common infectious entities in children. Here, we assessed the association between anemia and development of recurrent ARTI, UTI, and GE in children. This was a case-control study in hospitalized 2-5 years old children in Professorial Pediatric Unit at Teaching Hospital Anuradhapura, Sri Lanka. An 18-month follow up was done to assess the risk factors for the development of recurrent ARTI, GE, UTI, and control presented without infections. Further, 6-month follow up done after 3-month iron supplementation to assess the occurrence of recurrences. Blood Hb concentration was measured using Drabking's reagent. Logistic regression was used to find the risk factors for the development of recurrences. In ARTI, 121/165 (73.3%), GE, 88/124 (71%), UTI 46/96 (47.9%) and control 40/100 (40%) were having anemia. Initial ARTI group, recurrent ARTI was 24 (14.5%, p = 0.03); initial GE group: recurrent GE was 14 (11.3%, p = 0.03), recurrent ARTI was 11 (8.9%, p = 0.04); initial UTI group, development of; recurrent UTI was 8 (8.3%, p = 0.04); control, recurrent ARTI was 11 (11%, p = 0.03). Following 3-month iron supplementation reduction of recurrences was significant: initial ARTI recurrent ARTI in 90%, recurrent GE in 77.7%; initial GE recurrent GE in 83.3%, recurrent ARTI in 80%; initial UTI recurrent ARTI in 71.4% and control recurrent ARTI in 88.8%. Iron deficiency is a major type of anemia and anemic children are more prone to develop recurrent ARTI and GE. Once iron deficiency being corrected the rate of recurrent ARTI and GE was reduced. This would be a boost for policy developers to implement strategies at the community level to prevent iron deficiency in children to reduce ARTI and GE recurrences.
The interrelationship between hepcidin, vitamin D, and anemia in children with acute infectious disease.
Moran-Lev Hadar,Weisman Yosef,Cohen Shlomi,Deutsch Varda,Cipok Michal,Bondar Ekaterina,Lubetzky Ronit,Mandel Dror
BACKGROUND:Hepcidin is a master regulator of iron metabolism. Recently, it has been shown that vitamin D suppresses hepcidin expression. Our hypothesis was that hepcidin levels inversely correlate with vitamin D levels in anemic children during acute infection. METHODS:A prospective study was performed on 90 patients (45 females, 45 males, mean age 7.3 ± 5 years) who were admitted to the pediatric ward. Sixty-two patients had infectious disease (32 with coexisting anemia, 30 without anemia), and 28 patients were hospitalized for noninfectious causes. Blood samples for IL-6, hepcidin, iron status parameters, and 25-hydroxyvitamin D (25-OHD) were obtained within 72 h after admission. RESULTS:Serum concentrations of IL-6 and hepcidin were significantly higher and 25-OHD, iron, and transferrin were significantly lower in anemic children with infectious disease compared with controls. Children with a serum 25-OHD level < 20 ng/ml had significantly increased odds of having anemia than those with a level > 20 ng/ml (OR: 6.1, CI: 1.15-32.76). Correlation analyses found positive associations between hepcidin levels and ferritin (R = 0.47, P < 0.001) and negative associations between hepcidin and transferrin (R = 0.57, P < 0.001). CONCLUSION:Higher IL-6 and lower 25-OHD levels may lead to higher hepcidin levels and subsequently to hypoferremia and anemia in children with acute infection.
Markers of inflammation and activation of coagulation are associated with anaemia in antiretroviral-treated HIV disease.
Borges Álvaro H,Weitz Jeffrey I,Collins Gary,Baker Jason V,Lévy Yves,Davey Richard T,Phillips Andrew N,Neaton James D,Lundgren Jens D,Deeks Steven G,
AIDS (London, England)
OBJECTIVE:The objective of this study is to determine the relationship between inflammatory interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP)] and coagulation (D-dimer) biomarkers and the presence and type of anaemia among HIV-positive individuals. DESIGN:A cross-sectional study. METHODS:Combination antiretroviral therapy (cART)-treated adults participating in an international HIV trial with haemoglobin and mean corpuscular volume (MCV) measurements at entry were categorized by presence of anaemia (haemoglobin ≤14 g/dl in men and ≤12 g/dl in women) and, for those with anaemia, by type [microcytic (MCV < 80 fl), normocytic (80-100 fl), macrocytic (>100 fl)]. We analysed the association between inflammation (IL-6 and hsCRP) and coagulation (D-dimer) and haemoglobin, controlling for demographics (age, race and sex), BMI, HIV plasma RNA levels, CD4⁺ T-cell counts (nadir and baseline), Karnofsky score, previous AIDS diagnosis, hepatitis B/C coinfection and use of zidovudine. RESULTS:Among 1410 participants, 313 (22.2%) had anaemia. Of these, 4.1, 27.2 and 68.7% had microcytic, normocytic and macrocytic anaemia, respectively. When compared with participants with normal haemoglobin values, those with anaemia were more likely to be older, black, male and on zidovudine. They also had lower baseline CD4⁺ T-cell counts and lower Karnofsky scores. Adjusted relative odds of anaemia per two-fold higher biomarker levels were 1.22 (P = 0.007) for IL-6, 0.99 for hsCRP (P = 0.86) and 1.35 (P < 0.001) for D-dimer. Similar associations were seen in those with normal and high MCV values. CONCLUSION:Persistent inflammation and hypercoagulation appear to be associated with anaemia. Routine measurements of haemoglobin might provide insights into the inflammatory state of treated HIV infection.
S-Propargyl-Cysteine, a Novel Hydrogen Sulfide Donor, Inhibits Inflammatory Hepcidin and Relieves Anemia of Inflammation by Inhibiting IL-6/STAT3 Pathway.
Wang Minjun,Tang Wenbo,Xin Hong,Zhu Yi Zhun
Anemia of inflammation (AI) is clinically prevalent and greatly threatens public health. Traditional remedies have raised controversy during clinical practice, calling for alternative therapies. We have recently found that hydrogen sulfide (H2S) inhibits inflammatory hepcidin, the critical mediator of AI. However, due to the chemical property of H2S, there remains an urgent need for a stable H2S donor in AI treatment. Here we reported that S-propargyl-cysteine (SPRC), a novel water-soluble H2S donor, suppressed hepatic hepcidin and corrected hypoferremia induced by lipopolysaccharide. The effects of SPRC were reversed by inhibition of cystathionine γ-lyase, one of the major endogenous H2S synthases. Moreover, SPRC reduced serum hepcidin, improved transferrin saturation, and maintained erythrocyte membrane integrity in a chronic mouse AI model. Consistently, splenomegaly was ameliorated and splenic iron accumulation relieved. Mechanism study indicated that serum IL-6 content and hepatic Il-6 mRNA were decreased by SPRC, in parallel with reduced hepatic JAK2/STAT3 activation. On the whole, our data reveal the inhibition of inflammatory hepcidin by SPRC, and suggest SPRC as a potential remedy against AI.
Interleukin-6 G-174C polymorphism predicts higher risk of stroke in sickle cell anaemia.
Domingos Igor F,Pereira-Martins Diego A,Coelho-Silva Juan L,Borges-Medeiros Rayssa L,Falcão Diego A,Azevedo Renata C,Anjos Ana C,Costa Fernando F,Mendonça Taciana F,Cavalcanti Maria S,Araujo Aderson S,Lucena-Araujo Antonio R,Bezerra Marcos A
British journal of haematology
Elevated Serum Interleukin-6 Predicts Favorable Response to Immunosuppressive Therapy in Children With Aplastic Anemia.
Lu Shuanglong,Qiao Xiaohong,Xie Xiaotian
Journal of pediatric hematology/oncology
BACKGROUND:Immunosuppressive therapy (IST) is the standard treatment for aplastic anemia (AA) children who lack a sibling donor, but the clinical response rate to IST varies. Predictors of response to IST are valuable for stratifying AA patients and making clinical decisions. METHODS:The serum interleukin (IL)-6 levels of 41 AA patients were measured at the time of diagnosis and the response rate of the patients to IST was evaluated at 3, 6, and 12 months after IST. Receiver-operator characteristic (ROC) analysis was used to calculate the predictive value of initial IL-6 levels in determining response at 6 months after IST. RESULTS:The initial IL-6 levels were significant higher in responders than nonresponders at 6 months after IST (211.89 vs. 18.09 pg/mL; P=0.005), using 36.8 pg/mL as a threshold, there were 80% sensitivity and 81% specificity for discriminating responders and nonresponders to IST. Patients with initial high IL-6 level (>36.8 pg/mL) have favorable response rates than those with initial low IL-6 level (<36.8 pg/mL) at 3, 6, and 12 months after IST (P<0.01). CONCLUSION:High levels of IL-6 at the time of diagnosis predict a favorable response to IST in children with AA and this may be helpful for patient's stratification and clinical decisions.
Relationships among red cell distribution width, anemia, and interleukin-6 in adult congenital heart disease.
Miyamoto Kenji,Inai Kei,Takeuchi Daiji,Shinohara Tokuko,Nakanishi Toshio
Circulation journal : official journal of the Japanese Circulation Society
BACKGROUND:Red cell distribution width (RDW) is known to be associated with anemia and mortality in cardiovascular diseases, while anemia itself is related to increased mortality. RDW may also be related to cytokine activation. We investigated the potential of RDW to predict anemia-adjusted mortality in patients with adult congenital heart disease (ACHD) and we evaluated the relationships among RDW, anemia, and interleukin-6 (IL-6). METHODS AND RESULTS:This was a single-center, retrospective cohort study. Blood RDW and IL-6 levels were measured in 144 patients with ACHD (median age [interquartile range (IQR)], 28 [22-36] years), 84% in New York Heart Association class I/II. During a mean 4.8-year follow-up, 21 (15%) patients died of cardiovascular causes. Elevated RDW (>15.0%) correlated significantly with mortality risk in a univariate analysis (RDW hazard ratio [HR]: 1.570; 95% confidence interval [CI]: 1.208-2.040 per 1 standard deviation increase; P=0.001). Elevated RDW levels correlated significantly with increased anemia-adjusted mortality (adjusted RDW HR: 1.912; 95% CI: 1.369-2.670; P<0.001). The high RDW group had significantly elevated serum IL-6 levels (RDW >15%, median [IQR], 3.7 [0.9-13.9] pg/ml vs. RDW ≤15%, 1.4 [0.8-2.5 pg/ml]; P=0.001), as did patients with anemia (anemia, 1.9 [0.9-5.2] pg/ml vs. no anemia, 1.4 [0.8-2.5 pg/ml]; P=0.021). CONCLUSIONS:Elevation of RDW may be related with increased IL-6 and anemia-adjusted cardiovascular mortality in patients with ACHD.
Interleukin-6 and Interleukin-8 Levels Correlate With the Severity of Aplastic Anemia in Children.
Gupta Vineeta,Kumar Sushil,Sonowal Rimjhim,Singh Surya K
Journal of pediatric hematology/oncology
AIM:The aim of this study was to evaluate the levels of interleukin (IL)-6 and IL-8 in patients with aplastic anemia and its correlation with severity of the disease. MATERIALS AND METHODS:IL-6 and IL-8 levels were measured in 40 patients with aplastic anemia in the age group of 4 to 14 years. A total of 40 healthy children served as controls. Quantitative estimation of IL-6 and IL-8 was performed using a solid-phase sandwich ELISA kit. Results were presented as IL-6 and IL-8 concentrations in pg/mL. Patients received immunosuppressive therapy per the British Committee for Standards in Haematology Guidelines 2009. RESULTS:Mean age of the patients was 9.78±2.74 years. IL-6 level of patients was elevated compared with controls (193.48±352.3 vs. 4.58±3.39; P<0.001). IL-8 levels were also significantly elevated in patients compared with controls (15.58±18.0 vs. 1.85±0.95; P<0.001). IL levels were also assessed in relation to severity of the disease. Levels were the highest in patients with very severe aplastic anemia (724.33±519.42), followed by severe aplastic anemia (80.51±66.28 pg/mL), and non-severe aplastic anemia (6.01±1.89). Differences were statistically significant. A similar trend was also observed for IL-8 levels, where the levels were 41.02±24.23, 11.34±8.0, and 1.67±0.71 for very severe aplastic anemia, severe aplastic anemia, and non-severe aplastic anemia, respectively. The differences were again statistically significant. IL levels were also correlated with the treatment outcome. Responders had lower levels compared with nonresponders, but the difference was not statistically significant (186.36±322.45 vs. 198.74±368.10). Levels of ILs decreased in responders, but were not comparable with that of controls 6 months after therapy. CONCLUSIONS:High levels of IL-6 and IL-8 were observed in children with aplastic anemia. Increased levels showed correlation with disease severity and therefore appear to play an important role in aplastic anemia. However, levels had no significant correlation with the treatment outcome.
A panoramic review of IL-6: Structure, pathophysiological roles and inhibitors.
Kaur Sukhvir,Bansal Yogita,Kumar Raj,Bansal Gulshan
Bioorganic & medicinal chemistry
Interleukin-6 (IL-6) is a pleiotropic pro-inflammatory cytokine. Its deregulation is associated with chronic inflammation, and multifactorial auto-immune disorders. It mediates its biological roles through a hexameric complex composed of IL-6 itself, its receptor IL-6R, and glycoprotein 130 (IL-6/IL-6R/gp130). This complex, in turn, activates different signaling mechanisms (classical and trans-signaling) to execute various biochemical functions. The trans-signaling mechanism activates various pathological routes, like JAK/STAT3, Ras/MAPK, PI3K-PKB/Akt, and regulation of CD4+ T cells and VEGF levels, which cause cancer, multiple sclerosis, rheumatoid arthritis, anemia, inflammatory bowel disease, Crohn's disease, and Alzheimer's disease. Involvement of IL-6 in pathophysiology of these complex diseases makes it an important target for the treatment of these diseases. Though some anti-IL-6 monoclonal antibodies are being used clinically, but their high cost, only parenteral administration, and possibility of immunogenicity have limited their use, and warranted the development of novel small non-peptide molecules as IL-6 inhibitors. In the present report, all molecules reported in literature as IL-6 inhibitors have been classified as IL-6 production, IL-6R, and IL-6 signaling inhibitors. Reports available till date are critically studied to identify important and salient structural features common in these molecules. These analyses would assist medicinal chemists to design novel and potent IL-6 production and signaling inhibitors, through knowledge- and/or computer-based approaches, for the treatment of complex multifactorial diseases.
Pro-inflammatory cytokine interleukin-6-induced hepcidin, a key mediator of periodontitis-related anemia of inflammation.
Han Ye,Huang Wenxue,Meng Huanxin,Zhan Yalin,Hou Jianxia
Journal of periodontal research
OBJECTIVES:To investigate whether anemia of inflammation (AI) occurs in periodontitis patients and to further explore underlying pathogenesis of periodontitis-related AI by an experimental periodontitis model. BACKGROUND:Previous studies have reported periodontitis patients could show a tendency toward AI. However, the relationship between periodontitis and AI remains unclear, and the related pathological mechanisms have not been identified. MATERIALS AND METHODS:Periodontal clinical parameters, inflammatory markers, and anemia-related indicators were compared between 98 aggressive periodontitis (AgP) patients and 103 healthy subjects. An experimental periodontitis model was induced by ligature placement in mice. The changes in mice inflammatory markers, anemia indicators, hepcidin mRNA expression, and serum hepcidin concentrations were measured. Human and mouse liver cells were treated with interleukin-6 (IL-6) for analyzing the changes in hepcidin expression based on mRNA and protein levels. RESULTS:AgP patients exhibited higher white blood cell counts, IL-6, and C-reactive protein. Adjusted linear regression analyses showed correlations between AgP and decreased hemoglobin (HGB) and hematocrit (HCT). The ligature-induced periodontitis caused systemic inflammation and elevated IL-6 levels. Lower red blood cell counts, HGB, and HCT were detected, whereas the levels of hepcidin mRNA expression and serum hepcidin concentrations increased. The treatment of hepatocytes with IL-6 induced both hepcidin mRNA expression and hepcidin secretion. CONCLUSIONS:Systemic inflammation induced by periodontitis leads to an increased risk for AI. IL-6-induced hepcidin could play a central mediator role and act as a key pathologic mechanism. Our results demonstrate periodontitis may be considered as an additional inflammatory disease contributing to the development of AI.
Increased IL-6 and Potential IL-6 trans-signalling in the airways after an allergen challenge.
Esnault Stephane,Khosravi Mehdi,Kelly Elizabeth A,Liu Lin Ying,Bochkov Yury A,Tattersall Matthew C,Jarjour Nizar N
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
BACKGROUND:In asthma, IL-6 is a potential cause of enhanced inflammation, tissue damage and airway dysfunction. IL-6 signalling is regulated by its receptor, which is composed of two proteins, IL-6R and GP130. In addition to their membrane form, these two proteins may be found as extracellular soluble forms. The interaction of IL-6 with soluble IL-6R (sIL-6R) can trigger IL-6 trans-signalling in cells lacking IL-6R. Conversely, the soluble form of GP130 (sGP130) competes with its membrane form to inhibit IL-6 trans-signalling. OBJECTIVES:We aimed to analyse IL-6 trans-signalling proteins in the airways of subjects after an allergen challenge. METHODS:We used a model of segmental bronchoprovocation with an allergen (SBP-Ag) in human subjects with allergy. Before and 48 h after SBP-Ag, bronchoalveolar lavages (BALs) allowed for the analysis of proteins in BAL fluids (BALFs) by ELISA, and membrane proteins on the surface of BAL cells by flow cytometry. In addition, we performed RNA sequencing (RNA-seq) and used proteomic data to further inform on the expression of the IL-6R subunits by eosinophils, bronchial epithelial cells and lung fibroblasts. Finally, we measured the effect of IL-6 trans-signalling on bronchial fibroblasts, in vitro. RESULTS:IL-6, sIL-6R, sGP130 and the molar ratio of sIL-6R/sGP130 increased in the airways after SBP-Ag, suggesting the potential for enhanced IL-6 trans-signalling activity. BAL lymphocytes, monocytes and eosinophils displayed IL-6R on their surface and were all possible providers of sIL-6R, whereas GP130 was highly expressed in bronchial epithelial cells and lung fibroblasts. Finally, bronchial fibroblasts activated by IL-6 trans-signalling produced enhanced amounts of the chemokine, MCP-1 (CCL2). CONCLUSION AND CLINICAL RELEVANCE:After a bronchial allergen challenge, we found augmentation of the elements of IL-6 trans-signalling. Allergen-induced IL-6 trans-signalling activity can activate fibroblasts to produce chemokines that can further enhance inflammation and lung dysfunction.
Treatment with anti-IL-6 receptor antibody prevented increase in serum hepcidin levels and improved anemia in mice inoculated with IL-6-producing lung carcinoma cells.
Noguchi-Sasaki Mariko,Sasaki Yusuke,Shimonaka Yasushi,Mori Kazushige,Fujimoto-Ouchi Kaori
BACKGROUND:Hepcidin, a key regulator of iron metabolism, is produced mainly by interleukin-6 (IL-6) during inflammation. A mechanism linking cancer-related anemia and IL-6 through hepcidin production is suggested. To clarify the hypothesis that overproduction of IL-6 elevates hepcidin levels and contributes to the development of cancer-related anemia, we evaluated anti-IL-6 receptor antibody treatment of cancer-related anemia in an IL-6-producing human lung cancer xenograft model. METHODS:Nude mice were subcutaneously inoculated with cells of the IL-6-producing human lung cancer cell line LC-06-JCK and assessed as a model of cancer-related anemia. Mice bearing LC-06-JCK were administered rat anti-mouse IL-6 receptor antibody MR16-1 and their serum hepcidin levels and hematological parameters were determined. RESULTS:LC-06-JCK-bearing mice developed anemia according to the production of human IL-6 from xenografts, with decreased values of hemoglobin, hematocrit, and mean corpuscular volume (MCV) compared to non-tumor-bearing (NTB) mice. LC-06-JCK-bearing mice showed decreased body weight and serum albumin with increased serum amyloid A. MR16-1 treatment showed significant inhibition of decreased body weight and serum albumin levels, and suppressed serum amyloid A level. There was no difference in tumor volume between MR16-1-treated mice and immunoglobulin G (IgG)-treated control mice. Decreased hemoglobin, hematocrit, and MCV in LC-06-JCK-bearing mice was significantly relieved by MR16-1 treatment. LC-06-JCK-bearing mice showed high red blood cell counts and erythropoietin levels as compared to NTB mice, whereas MR16-1 treatment did not affect their levels. Serum hepcidin and ferritin levels were statistically elevated in mice bearing LC-06-JCK. LC-06-JCK-bearing mice showed lower values of MCV, mean corpuscular hemoglobin (MCH), and serum iron as compared to NTB mice. Administration of MR16-1 to mice bearing LC-06-JCK significantly suppressed levels of both serum hepcidin and ferritin, with increased values of MCV and MCH. CONCLUSIONS:Our results suggest that overproduction of hepcidin by IL-6 signaling might be a major factor that leads to functionally iron-deficient cancer-related anemia in the LC-06-JCK model. We demonstrated that inhibition of the IL-6 signaling pathway by MR16-1 treatment resulted in significant recovery of iron-deficiency anemia and alleviation of cancer-related symptoms. These results indicate that IL-6 signaling might be one possible target pathway to treat cancer-related anemia disorders.