Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0240066 (iron deficiency)
 7,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The most common cause of limited response to recombinant human erythropoietin (r-HuEPO) is unrecognized, mild-to-moderate iron deficiency, either at the start of treatment or secondary to enhanced iron utilization by newly formed erythrocytes. Iron stores in patients with chronic renal failure (CRF) are often depleted through gastrointestinal bleeding, blood loss during haemodialysis, and blood sampling. Mobilization of iron stores may be inadequate, especially during rapid haemoglobin regeneration. Aluminium overload may also interfere with gastrointestinal and cellular iron uptake. Overt or unrecognized infection or inflammation is another common cause of hyporesponsiveness, and is a consequence of increased blood concentrations of cytokines such as tumour necrosis factor (TNF), interleukin-1 (IL-1), and interferon-gamma (IFN-gamma), which suppress erythrocyte stem-cell proliferation. Less common causes include severe secondary hyperparathyroidism and myeloma (during chemotherapy). Response to r-HuEPO can be best predicted by baseline fibrinogen (a marker of subclinical inflammation); baseline transferrin receptor (sTfR) concentrations (a marker of functional iron deficiency); and sTfR increment after 2 weeks (a marker of early change in erythropoietic activity).
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PMID:R-HuEPO hyporesponsiveness--who and why? 764 9

Inflammatory low iron is the second cause, after true iron deficiency, of acquired anaemia. It is mainly due to insufficient erythropoiesis resulting from inhibition of the erythroid progenitor and to disturbances in the synthesis and action of erythropoietin. These changes seem to be dependent on factors, such as TNF-alpha, interleukin-1 and interferon-gamma, which are released in inflammatory processes. Alterations in iron metabolism seem to be secondary, but also partly provoked by the same inhibitory agents. All these anaemias share a common character, i.e. lowering of serum iron level without increase of transferrin level, while plasma ferritin level is within normal limits. In addition to symptomatic therapy by red cell transfusions, numerous trials have shown that recombinant erythropoietin is effective in the treatment of the anaemia that accompanies cancers, chronic inflammatory and rheumatic diseases and of the anaemia provoked by HIV infection.
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PMID:[Inflammatory hyposideremic anemia]. 823 81

Patients receiving epoetin therapy show wide variability in their responsiveness to the drug. Many factors may be responsible for this, particularly iron deficiency, acute infection and under-dialysis. Even after excluding factors known to cause resistance to epoetin, the marked variability in sensitivity to epoetin remains. The exact mechanism of this effect is unclear. It is, however, recognized that uraemia is a chronic inflammatory state, with some patients showing quite significantly increased laboratory markers of inflammation and immune activation. It is also known that chronic inflammation can modify the process of erythropoiesis, and this is probably mediated via pro-inflammatory cytokines such as interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). It is hypothesized, therefore, that some patients showing resistance to epoetin may have enhanced levels of immune activation, causing increased release of pro-inflammatory cytokines in the bone marrow. This has been investigated by studying T-cell phenotypes by flow cytometry, along with cytokine release from T cells and monocytes in 'good' and 'poor' responders to epoetin. Poor responders were found to have significantly reduced CD28 expression on both CD4(+) and CD8(+) cells, enhanced IL-10 generation from peripheral blood mononuclear cells (PBMCs), higher plasma IL-12 levels and enhanced TNF-alpha release from PBMCs. The patients in this study, who were followed-up for the subsequent 24 months, had a considerably lower survival if they were poor responders (54% vs 88% for good responders; P<0.05). Further work in this area is required to confirm or contest the hypothesis that epoetin resistance is due to enhanced levels of immune activation.
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PMID:The inflammatory response and epoetin sensitivity. 1181 13

Up to 10% of patients with renal disease receiving recombinant human erythropoietin (rHuEPO) therapy show poor responsiveness to the drug. Even in patients who do respond to rHuEPO, there is a marked variability in drug sensitivity. Several factors have been recognized as causing resistance to rHuEPO, notably iron deficiency, infection/inflammation, and under dialysis. However, when these factors are excluded, the wide variation in responsiveness to rHuEPO persists. The mechanism of this effect needs to be fully elucidated. One hypothesis is that patients with uraemia showing resistance to rHuEPO may have enhanced levels of immune activation, causing increased release of pro-inflammatory cytokines in the bone marrow. Uraemia is known to be a chronic inflammatory state, with some patients showing considerably increased laboratory markers of inflammation and immune activation. Chronic inflammation can modify the process of erythropoiesis, probably mediated via pro-inflammatory cytokines such as interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). The concept that rHuEPO resistance is due to enhanced levels of immune activity has been investigated by studying T-cell phenotypes using flow cytometry, as well as cytokine release from T cells and monocytes in 'good' and 'poor' responders to rHuEPO. Poor responders had significantly reduced CD28 expression on both CD4+ and CD8+ cells, enhanced IL-10 generation from peripheral blood mononuclear cells (PBMCs), higher plasma IL-12 levels, and increased TNF-alpha and IFN-gamma release from PBMCs. Anti-cytokine antibodies may be useful for studying inflammatory cytokine secretion from T cells in patients with renal failure. Strategies utilizing anti-cytokine therapy may prove to be a useful adjuvant in optimizing the response to rHuEPO therapy.
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PMID:Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines. 1238 57

Resistance to recombinant human erythropoietin occurs in a small but important proportion of hemodialysis patients. This may be due to increased immune activation because pro-inflammatory cytokines inhibit erythropoiesis in vitro. Using FACScan flow cytometry, the proportion of PMA/ionomycin-stimulated T cells expressing cytokines ex vivo was compared in 18 poor responders to erythropoietin, 14 good responders to erythropoietin, and 14 normal controls. CD4(+) T cells from poor responders expressed more interferon-gamma (IFN-gamma; 19 +/- 6%) compared with good responders (11 +/- 6%, P < 0.001) and controls (12 +/- 6%, P < 0.01). Similarly, CD4+ T cells from poor responders expressed more tumor necrosis factor-alpha (TNF-alpha; poor responders: 51 +/- 19% versus good responders: 27 +/- 15% [P < 0.01] and controls: 30 +/- 19% [P < 0.01]). CD4+ expression of IL-10 was also enhanced (poor responders: 1.6 +/- 1.1% versus good responders: 0.7 +/- 0.6% [P < 0.05] and controls: 0.5 +/- 0.2% [P < 0.01]). Likewise, CD4+ expression of interleukin-13 (IL-13) was increased (poor responders: 4.4 +/- 4.2% versus good responders: 1.6 +/- 1.7% [P < 0.05] and controls: 1.6 +/- 1.5% [P < 0.05]). CD8+ T cells from poor responders also showed enhanced expression of cytokines. For IFN-gamma, poor responder expression was 48 +/- 20% compared with 31 +/- 17% (P < 0.05) for good responders and 23 +/- 15% (P < 0.01) for controls. TNF-alpha expression for poor responders was 41 +/- 21% versus 25 +/- 14% for good responders (P < 0.05) and 21 +/- 15% for controls (P < 0.01). IL-10 expression for poor responders was 2.0 +/- 1.2% (good responders: 0.7 +/- 0.6% [P < 0.01]; controls: 0.5 +/- 0.2% [P < 0.001]). These data indicate that T cells from poor responders are in an enhanced activation state possibly as a result of chronic inflammation. In the absence of any other cause (such as iron deficiency), the overproduction of cytokines may account for hyporesponsiveness to erythropoietic therapy in patients with renal failure.
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PMID:Increased expression of erythropoiesis inhibiting cytokines (IFN-gamma, TNF-alpha, IL-10, and IL-13) by T cells in patients exhibiting a poor response to erythropoietin therapy. 1281 37

Interleukin (IL)-10 plays crucial regulatory roles in immune responses by inhibiting the secretion of several cytokines (IL-2, IL-12, interferon-gamma (IFN-gamma)) and lymphocyte proliferation. Iron deficiency, a public health problem for children, alters these immune responses. To determine whether these changes are related to altered IL-10 secretion, we measured IL-10 in 24 and 48 h supernatant of spleen cell cultures from iron deficient (ID), control (C), pairfed (PF), and ID mice fed the control diet (iron repletion) for 3 (R3) and 14 (R14) days (d, n = 12/group). Mean levels of hemoglobin, hematocrit, and liver iron stores varied as follows: C approximately equal PF approximately equal R14 > R3 > ID (P < 0.01). Mean baseline IL-10 levels of ID mice tended to be higher than those of other groups (P > 0.05, ANOVA). Mean IL-10 levels secreted by concanavalin A (Con A) and antibody raised against cluster of differentiation molecule 3 (anti-CD3)-treated cells (+/-background) were lower in ID than in C (48 h) and iron replete mice (P < 0.05). Underfeeding also reduced IL-10 secretion by anti-CD3-treated cells (48 h, P < 0.05). Lymphocyte proliferative responses to anti-CD3 +/- anti-CD28 antibodies were lower in ID than in C and PF mice, and they were corrected by iron repletion (P < 0.05). IL-10 levels negatively correlated with indicators of iron status (r <or= -0.285) and lymphocyte proliferation (r <or= -0.379 [r <or= -0.743 for ID mice]), but positively correlated with IFN-gamma levels (r <or= 0.47; P < 0.05). Data suggest that iron deficiency has a generalized deleterious effect on cells that secrete both cytokines. Reduced IL-10 secretion by activated cells does not overcome the inhibition of lymphocyte proliferation due to other factors of T cell activation that are regulated by iron.
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PMID:Effects of iron deficiency on the secretion of interleukin-10 by mitogen-activated and non-activated murine spleen cells. 1450 44