Anemia of inflammation Roy, Cindy N
Hematology,
2010, Letnik:
2010, Številka:
1
Journal Article
Odprti dostop
Inflammation arising from various etiologies, including infection, autoimmune disorders, chronic diseases, and aging, can promote anemia. The anemia of inflammation (AI) is most often normocytic and ...normochromic and is usually mild. Characteristic changes in systemic iron handling, erythrocyte production, and erythrocyte life span all contribute to AI. The preferred treatment is directed at the underlying disease. However, when the inflammatory insult is intractable, or the cause has not been diagnosed, there are limited options for treatment of AI. Because anemia is a comorbid condition that is associated with poor outcomes in various chronic disease states, understanding its pathogenesis and developing new tools for its treatment should remain a priority. Hepcidin antimicrobial peptide has taken center stage in recent years as a potent modulator of iron availability. As the technology for quantitative hepcidin analysis improves, hepcidin's role in various disease states is also being revealed. Recent insights concerning the regulatory pathways that modify hepcidin expression have identified novel targets for drug development. As the field advances with such therapeutics, the analysis of the impact of normalized hemoglobin on disease outcomes will confirm whether anemia is a reversible independent contributor to the morbidity and mortality associated with inflammatory diseases.
Summary Background & aims Red cell distribution width (RDW), a measure of heterogeneity in the size of circulating erythrocytes, is associated with some chronic diseases and predicts mortality. ...Although oxidative damage and inflammation have been theorized to affect RDW, the relationships of antioxidants and inflammation with RDW have not been well characterized. The aims were to determine whether total serum carotenoids, α-tocopherol, selenium, protein carbonyls, and interleukin-6 (IL-6) are associated with RDW and predict RDW over time. Methods RDW was measured at baseline, 12 months, and 24 months follow-up in 786 moderately to severely disabled community-dwelling women, aged ≥65 years, in the Women's Health and Aging Study I in Baltimore, Maryland. Results Selenium was significantly associated with RDW at baseline and predicted RDW over two years' follow-up in separate multivariate mixed-effects models that adjusted for other covariates. As expected, the addition of IL-6 to the models attenuated the association of serum selenium with RDW, as low antioxidant levels are known to upregulate IL-6. Total carotenoids were associated with RDW at baseline and one year follow-up. Protein carbonyls and α-tocopherol were not significantly associated with RDW. Conclusion Serum selenium is an independent predictor of RDW and may potentially mediate effects on RDW through IL-6.
Anemia in frailty Roy, Cindy N
Clinics in geriatric medicine,
02/2011, Letnik:
27, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Although anemia is regarded as a relatively common occurrence in older adults, the vigor with which the medical community should intervene to correct this common problem is disputed. Epidemiologic ...data clearly correlate anemia with functional decline, disability, and mortality. Anemia may contribute to functional decline by restricting oxygen delivery to muscle, or to cognitive decline by restricting oxygen delivery to the brain. On the other hand, the erythron may be a separate target of the same biologic mediators that influence deterioration of physiologic systems that contribute to weakness, functional and cognitive decline, and mortality. Clinical trials aimed at treating anemia in older adults could assess whether physical performance is improved or whether mortality risk declines with improved hemoglobin, but sufficient evidence from such trials is currently lacking. With few guidelines regarding treatment of older adults and significant risk for adverse events associated with transfusion and erythroid stimulating agents, anemia often goes untreated or ignored in geriatric clinics. This article reviews the problem of anemia in older adults, with a particular emphasis on the frail elderly. The gaps in the evidence base for the treatment of anemia in older adults are reviewed and the options for advancing the field are assessed.
IMPORTANCE: In one-third of older men with anemia, no recognized cause can be found. OBJECTIVE: To determine if testosterone treatment of men 65 years or older with unequivocally low testosterone ...levels and unexplained anemia would increase their hemoglobin concentration. DESIGN, SETTING, AND PARTICIPANTS: A double-blinded, placebo-controlled trial with treatment allocation by minimization using 788 men 65 years or older who have average testosterone levels of less than 275 ng/dL. Of 788 participants, 126 were anemic (hemoglobin ≤12.7 g/dL), 62 of whom had no known cause. The trial was conducted in 12 academic medical centers in the United States from June 2010 to June 2014. INTERVENTIONS: Testosterone gel, the dose adjusted to maintain the testosterone levels normal for young men, or placebo gel for 12 months. MAIN OUTCOMES AND MEASURES: The percent of men with unexplained anemia whose hemoglobin levels increased by 1.0 g/dL or more in response to testosterone compared with placebo. The statistical analysis was intent-to-treat by a logistic mixed effects model adjusted for balancing factors. RESULTS: The men had a mean age of 74.8 years and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 30.7; 84.9% were white. Testosterone treatment resulted in a greater percentage of men with unexplained anemia whose month 12 hemoglobin levels had increased by 1.0 g/dL or more over baseline (54%) than did placebo (15%) (adjusted OR, 31.5; 95% CI, 3.7-277.8; P = .002) and a greater percentage of men who at month 12 were no longer anemic (58.3%) compared with placebo (22.2%) (adjusted OR, 17.0; 95% CI, 2.8-104.0; P = .002). Testosterone treatment also resulted in a greater percentage of men with anemia of known cause whose month 12 hemoglobin levels had increased by 1.0 g/dL or more (52%) than did placebo (19%) (adjusted OR, 8.2; 95% CI, 2.1-31.9; P = .003). Testosterone treatment resulted in a hemoglobin concentration of more than 17.5 g/dL in 6 men who had not been anemic at baseline. CONCLUSIONS AND RELEVANCE: Among older men with low testosterone levels, testosterone treatment significantly increased the hemoglobin levels of those with unexplained anemia as well as those with anemia from known causes. These increases may be of clinical value, as suggested by the magnitude of the changes and the correction of anemia in most men, but the overall health benefits remain to be established. Measurement of testosterone levels might be considered in men 65 years or older who have unexplained anemia and symptoms of low testosterone levels. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00799617
Summary
Developed countries, such as the United Kingdom, are experiencing a change in demographics resulting in the largest proportion of adults over 65 years of age that our health systems have ever ...experienced. As such, haematologists must be prepared to evaluate and treat anaemia in a more complicated patient population, but sufficient evidence‐based guidelines are lacking. Critical next steps that must be taken to ensure the best care of this population include the determination of appropriate haemoglobin concentrations for older adults in light of age, gender, race, and comorbidities; the development of interventional trials that address physical performance outcomes in addition to haemoglobin targets; and translational studies which address the molecular pathogenesis of anaemia in older adults with the most advanced scientific approaches.
The anemia of inflammation is an acquired disorder affecting patients with a variety of medical conditions, and it is characterized by changes in iron homeostasis and erythropoiesis. Mounting ...evidence suggests that hepcidin antimicrobial peptide plays a primary role in the pathogenesis of the anemia of inflammation. To evaluate which features of this anemia can be attributed to hepcidin, we have generated mice carrying a tetracycline-regulated hepcidin transgene. Expression of the hepcidin transgene resulted in down-regulation of endogenous hepcidin mRNA. The transgenic mice developed a mild-to-moderate anemia associated with iron deficiency and iron-restricted erythropoiesis. Similar to the anemia of inflammation, iron accumulated in tissue macrophages, whereas a relative paucity of iron was found in the liver. Circulating erythrocytes in transgenic animals had normal survival rates, but transgenic animals had an impaired response to erythropoietin. Thus, hepcidin transgenic mice recapitulate each of the key features of anemia of inflammation in human patients and serve as a useful model of this prevalent disorder.
Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. Serial analyses of β-thalassemic mice indicate that while hemoglobin levels ...decrease over time, the concentration of iron in the liver, spleen, and kidneys markedly increases. Iron overload is associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Patients with β-thalassemia also have low hepcidin levels. These observations led us to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis and that increasing the concentration of hepcidin in the body of such patients might be therapeutic, limiting iron overload. Here we demonstrate that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. These data led us to suggest that therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.
Summary
Testosterone administration increases hemoglobin levels and has been used to treat anemia of chronic disease. Erythrocytosis is the most frequent adverse event associated with testosterone ...therapy of hypogonadal men, especially older men. However, the mechanisms by which testosterone increases hemoglobin remain unknown. Testosterone administration in male and female mice was associated with a greater increase in hemoglobin and hematocrit, reticulocyte count, reticulocyte hemoglobin concentration, and serum iron and transferrin saturation than placebo. Testosterone downregulated hepatic hepcidin mRNA expression, upregulated renal erythropoietin mRNA expression, and increased erythropoietin levels. Testosterone‐induced suppression of hepcidin expression was independent of its effects on erythropoietin or hypoxia‐sensing mechanisms. Transgenic mice with liver‐specific constitutive hepcidin over‐expression failed to exhibit the expected increase in hemoglobin in response to testosterone administration. Testosterone upregulated splenic ferroportin expression and reduced iron retention in spleen. After intravenous administration of transferrin‐bound 58Fe, the amount of 58Fe incorporated into red blood cells was significantly greater in testosterone‐treated mice than in placebo‐treated mice. Serum from testosterone‐treated mice stimulated hemoglobin synthesis in K562 erythroleukemia cells more than that from vehicle‐treated mice. Testosterone administration promoted the association of androgen receptor (AR) with Smad1 and Smad4 to reduce their binding to bone morphogenetic protein (BMP)‐response elements in hepcidin promoter in the liver. Ectopic expression of AR in hepatocytes suppressed hepcidin transcription; this effect was blocked dose‐dependently by AR antagonist flutamide. Testosterone did not affect hepcidin mRNA stability. In conclusion, testosterone inhibits hepcidin transcription through its interaction with BMP/Smad signaling. Testosterone administration is associated with increased iron incorporation into red blood cells.
Vitamin D, Race, and Risk for Anemia in Children Atkinson, Meredith A., MD, MHS; Melamed, Michal L., MD, MHS; Kumar, Juhi, MD, MPH ...
The Journal of pediatrics,
01/2014, Letnik:
164, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Objective To examine the association between 25-hydroxyvitamin D 25(OH)D deficiency and anemia in a cohort of otherwise-healthy children and to determine whether race modifies the association between ...25(OH)D status and hemoglobin (Hgb). Study design Cross-sectional study of 10 410 children and adolescents ages 1-21 years from the 2001-2006 National Health and Nutrition Examination Survey. Anemia was defined as Hgb less than the 5th percentile for age and sex based on National Health and Nutrition Examination Survey III (1988-1994) data. Results Lower 25(OH)D levels were associated with increased risk for anemia; <30 ng/mL, adjusted OR 1.93, 95% CI 1.21-3.08, P = .006, and <20 ng/mL, OR 1.47, 95% CI 1.14-1.89, P = .004. In linear regression, small but significant increases in Hgb were noted in the upper quartiles of 25(OH)D compared with the lowest quartile (<20 ng/mL) in the full cohort. Results of race-stratified linear regression by 25(OH)D quartile in white children were similar to those observed in the full cohort, but in black children, an increase in Hgb in the upper 25(OH)D quartiles was only apparent compared with the lowest black race−specific quartile (<12 ng/mL). Conclusion 25(OH)D deficiency is associated with increased risk of anemia in healthy US children, but the 25(OH)D threshold levels for lower Hgb are lower in black children in comparison with white children.
BMSCs are critical regulators of the hematopoietic response to inflammation through secretion of IL‐6.
Inflammation alters hematopoiesis, often by decreasing erythropoiesis and enhancing myeloid ...output. The mechanisms behind these changes and how the BM stroma contributes to this process are active areas of research. In this study, we examine these questions in the setting of murine Toxoplasma gondii infection. Our data reveal that infection alters early myeloerythroid differentiation, blocking erythroid development beyond the Pre MegE stage, while expanding the GMP population. IL‐6 was found to be a critical mediator of these differences, independent of hepcidin‐induced iron restriction. Comparing the BM with the spleen showed that the hematopoietic response was driven by the local microenvironment, and BM chimeras demonstrated that radioresistant cells were the relevant source of IL‐6 in vivo. Finally, direct ex vivo sorting revealed that VCAM+CD146lo BM stromal fibroblasts significantly increase IL‐6 secretion after infection. These data suggest that BMSCs regulate the hematopoietic changes during inflammation via IL‐6.
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