Direct suppression/blockade of hepcidin activity
Anti-hepcidin antibodies.
Experiments in vitro and in vivo in a murine model of ACD suggest that suppression or inhibition of hepcidin expression may be a possible means of improving ACD: overexpression of human hepcidin in mice produces a picture of anemia similar to that seen in ACD, with resistance to exogenous EPO therapy, and mice rendered anemic by heat-killed Brucella abortus were effectively treated by hepcidin mRNA suppression. Treatment of mice overexpressing human hepcidin with anti-hepcidin antibodies did not by itself lead to resolution of treated animals, but did restore sensitivity to treatment with EPO.
Indirect suppression of hepcidin
Dorsomorphin is a small molecule inhibitor of BMP signalling that was identified during screening of compounds that dorsalize zebrafish embryos. In vitro experiments showed inhibition by dorsomorphin of BMP, IL-6 and haemojuvelin-stimulated expression of hepcidin, and in vivo inhibition of iron-stimulated expression of hepcidin mRNA in zebrafish, and induction of hyperferremia in iron-replete mice, suggesting a possible role in reducing elevated hepcidin levels in ACD.
Similarly, in a murine model of inflammatory bowel disease, inhibition of BMP by HJV.Fc, a recombinant protein that prevents binding of BMPs to their receptor, LDN-193189, a small molecule inhibitor of BMP signal transduction, and an anti-BMP-6 antibody, inhibited hepcidin expression and increased serum iron levels.
Finally, heparin is known to bind BMPs, and can variably modulate their signalling effects: exogenous heparin has recently been shown to downregulate hepcidin expression by the hepatoma cell line, HepG2 in a dose-dependent manner, and at pharmacological concentrations. Treatment of mice with heparin inhibited liver hepcidin mRNA expression and SMAD phosphorylation, reduced spleen iron concentration, and increased serum iron. Administration of heparin to five patients with deep venous thrombosis also produced reductions in hepcidin levels. The authors postulated that the effects of heparin in their study were mediated by sequestration of BMP proteins, with formation of complexes that are unable to stimulate SMAD signalling and hepcidin expression, and further studies of its potential in improving haemoglobin levels in patients with ACD seem warranted for this widely used agent.
Anti-IL-6 receptor antibodies.
Castleman disease is a rare lymphoproliferative disorder characterized by hyperplastic lymph nodes showing follicular hyperplasia and capillary proliferation associated with endothelial hyperplasia. Dysregulated production of IL-6 has been shown to be responsible for some of the systemic manifestations of the multicentric form of the disease. Five out of six patients receiving longterm treatment with an anti-IL-6 receptor antibody, tocilizumab, showed rapid reductions in serum hepcidin levels, and a more gradual, but progressive, improvement in hematological parameters, including anemia, was observed in nine patients. Anti-IL-6 receptor blockade may represent a future targeted therapy for ACD.
Vitamin D.
A recent study has shown an association between vitamin D deficiency and ACD in the elderly: the Third National Health and Nutrition Examination Study (NHANES III) examined health and nutritional status of non-institutionalized subjects over 60 years of age in the United States, and hemoglobin and vitamin D levels were obtained in 5100 and 4575 subjects respectively. A significant correlation between hemoglobin and vitamin D levels was found. Further analysis of a subset of 2610 patients, who had more detailed hematological data available, showed that this association was particularly strong for patients with ACD. Individuals with ACD were twice as likely to have vitamin D deficiency as non-anemic subjects. It remains to be seen if there is an etological link between vitamin D deficiency and ACD, and whether vitamin D replenishment will have any therapeutic role to play.
Pentoxifylline.
Pentoxifylline is a drug with anti-inflammatory properties, and can suppress production of TNF-alpha and IFN-gamma. Two studies have suggested a beneficial effect for this agent in chronic renal failure patients with anemia resistant to EPO: parallel reductions in pro-inflammatory cytokine levels suggested that the mechanism for this effect was via the anti-inflammatory effects of this agent, and future studies in ACD may be worthwhile.
Showing posts with label CLL anemia. Show all posts
Showing posts with label CLL anemia. Show all posts
Monday, August 15, 2011
Sunday, August 14, 2011
The role of iron in ACD
Iron therapy
The recognition of the role of functional iron deficiency in the pathogenesis of ACD, together with the development of new formulations of parenteral iron, have led to a re-evaluation of iron supplementation in the management of this anemia. As already discussed, IDA frequently co-exists with ACD, and it is clearly important that true deficiency of iron is corrected. However, even in patients with ‘pure’ ACD, iron supplementation may theoretically be beneficial. Iron deficiency may also develop during the treatment of ACD with EPOs and limit the hematological response to these agents.
Oral iron supplements are often poorly tolerated, and patients frequently show poor compliance: in addition, patients with ACD will usually have raised hepcidin levels, which would be expected to inhibit intestinal iron absorption. However, oral iron is cheap, widely available, and easy to give, and given the difficulties in ruling out concomitant IDA in many patients with ACD, a trial of oral iron will be undertaken by many clinicians treating ACD. It must however be recognized that failure to respond to oral iron rules out neither true, nor functional iron deficiency.
There is little literature on the use of intravenous iron supplementation alone in the treatment of ACD. Cazzola et al on the beneficial effects of intravenous iron in 20 consecutive patients with juvenile chronic arthritis, although it is likely that a significant proportion of these patients also had true iron deficiency. Studies in patients with gynaecological cancer also showed a benefit in terms of reduced transfusion requirements for those receiving intravenous iron supplementation. However baseline iron status was not reported in either of these papers, and clearly larger studies are needed.
Much of the literature concerning intravenous iron supplementation has come from the field of renal medicine, where the superiority of parenteral over oral iron supplementation is now well established, and not only improves the responses to EPOs but can also lead to reduced doses of EPOs being used. The DRIVE (Dialysis Patients’ Response to IV iron and with Elevated Ferritin) trial randomized selected hemodialysis patients with elevated ferritin and reduced transferrin saturation to receive or not receive intravenous ferric gluconate together with EPO. The patients who received IV iron showed more rapid and better responses in Hb level than the controls, and similar responses were seen in patients with transferrin saturations above and below 19%, leading the authors to conclude that functional iron deficiency was a significant contributor to anemia in this setting, and that this could be overcome by intravenous iron supplementation.
There is now evidence that intravenous iron can enhance the effects of EPOs in patients with other forms of ACD, particularly cancer-related anemia. Auerbach et al randomized 155 patients being treated with EPOs for chemotherapy-related anaemia to no iron, oral iron or intravenous iron: there were significant improvements in hematological responses in patients receiving intravenous iron compared with those receiving either no iron or oral iron. These observations have been confirmed in several subsequent studies. Criteria for exclusion of co-existent IDA varied between these trials, and it is possible that significant numbers of patients included were in fact iron deficient, but the study by Hedenus et al is of particular interest as it enrolled only patients with lymphoproliferative malignancies not receiving chemotherapy, and all patients had detectable bone marrow iron stores.
In contrast, a recent study by Steensma et al randomized patients with chemotherapy-associated anemia to no iron, oral iron or intravenous iron plus darbepoietin: all had serum ferritin >20 μg/l and transferrin saturations <60%. There was no difference in erythropoietic response between the three groups. The mean pre-treatment ferritin levels in this study were higher than in the other studies, suggesting this population was less likely to have co-existent IDA, and the doses and scheduling of iron infusions were lower. Both these observations may partly explain the different results observed, but it is clear that further prospective studies, with better characterization of baseline iron stores are needed to define the role of intravenous iron supplementation in this setting. The ASH/ASCO guidelines recommend periodic monitoring of iron status in patients receiving treatment with EPOs but fall short of recommending intravenous supplementation to augment responses.
It is not yet known how intravenous iron might overcome the reticuloendothelial blockade on iron utilization thought to be fundamental to the pathogenesis of ACD, but it is possible that the infused iron may become bound directly to transferrin rather than being taken up by macrophages, and is thus available to the erythron. There are however no in vitro data to support this hypothesis.
Safety issues also need to be considered when using intravenous iron, particularly as older preparations were associated with significant adverse events, including anaphylaxis. Recent pharmacological developments have led to the release of several new iron formulations including low molecular weight iron dextran (Cosmofer), iron sucrose (Venofer), ferric carboxymaltose (Ferinject) and sodium ferric gluconate (Ferrlecit). In the trials above, no excess of adverse effects was observed with these newer intravenous iron preparations. One hypothesis for the hypoferremia seen in ACD is that low iron levels might inhibit bacterial growth, as iron is essential for the growth and survival of intracellular bacteria, but there is no evidence to date that supplemental iron increases the risk of infections. However, the long-term effects of intravenous iron administration on other parameters, for example tumor growth and cardiovascular disease, have not been studied.
The recognition of the role of functional iron deficiency in the pathogenesis of ACD, together with the development of new formulations of parenteral iron, have led to a re-evaluation of iron supplementation in the management of this anemia. As already discussed, IDA frequently co-exists with ACD, and it is clearly important that true deficiency of iron is corrected. However, even in patients with ‘pure’ ACD, iron supplementation may theoretically be beneficial. Iron deficiency may also develop during the treatment of ACD with EPOs and limit the hematological response to these agents.
Oral iron supplements are often poorly tolerated, and patients frequently show poor compliance: in addition, patients with ACD will usually have raised hepcidin levels, which would be expected to inhibit intestinal iron absorption. However, oral iron is cheap, widely available, and easy to give, and given the difficulties in ruling out concomitant IDA in many patients with ACD, a trial of oral iron will be undertaken by many clinicians treating ACD. It must however be recognized that failure to respond to oral iron rules out neither true, nor functional iron deficiency.
There is little literature on the use of intravenous iron supplementation alone in the treatment of ACD. Cazzola et al on the beneficial effects of intravenous iron in 20 consecutive patients with juvenile chronic arthritis, although it is likely that a significant proportion of these patients also had true iron deficiency. Studies in patients with gynaecological cancer also showed a benefit in terms of reduced transfusion requirements for those receiving intravenous iron supplementation. However baseline iron status was not reported in either of these papers, and clearly larger studies are needed.
Much of the literature concerning intravenous iron supplementation has come from the field of renal medicine, where the superiority of parenteral over oral iron supplementation is now well established, and not only improves the responses to EPOs but can also lead to reduced doses of EPOs being used. The DRIVE (Dialysis Patients’ Response to IV iron and with Elevated Ferritin) trial randomized selected hemodialysis patients with elevated ferritin and reduced transferrin saturation to receive or not receive intravenous ferric gluconate together with EPO. The patients who received IV iron showed more rapid and better responses in Hb level than the controls, and similar responses were seen in patients with transferrin saturations above and below 19%, leading the authors to conclude that functional iron deficiency was a significant contributor to anemia in this setting, and that this could be overcome by intravenous iron supplementation.
There is now evidence that intravenous iron can enhance the effects of EPOs in patients with other forms of ACD, particularly cancer-related anemia. Auerbach et al randomized 155 patients being treated with EPOs for chemotherapy-related anaemia to no iron, oral iron or intravenous iron: there were significant improvements in hematological responses in patients receiving intravenous iron compared with those receiving either no iron or oral iron. These observations have been confirmed in several subsequent studies. Criteria for exclusion of co-existent IDA varied between these trials, and it is possible that significant numbers of patients included were in fact iron deficient, but the study by Hedenus et al is of particular interest as it enrolled only patients with lymphoproliferative malignancies not receiving chemotherapy, and all patients had detectable bone marrow iron stores.
In contrast, a recent study by Steensma et al randomized patients with chemotherapy-associated anemia to no iron, oral iron or intravenous iron plus darbepoietin: all had serum ferritin >20 μg/l and transferrin saturations <60%. There was no difference in erythropoietic response between the three groups. The mean pre-treatment ferritin levels in this study were higher than in the other studies, suggesting this population was less likely to have co-existent IDA, and the doses and scheduling of iron infusions were lower. Both these observations may partly explain the different results observed, but it is clear that further prospective studies, with better characterization of baseline iron stores are needed to define the role of intravenous iron supplementation in this setting. The ASH/ASCO guidelines recommend periodic monitoring of iron status in patients receiving treatment with EPOs but fall short of recommending intravenous supplementation to augment responses.
It is not yet known how intravenous iron might overcome the reticuloendothelial blockade on iron utilization thought to be fundamental to the pathogenesis of ACD, but it is possible that the infused iron may become bound directly to transferrin rather than being taken up by macrophages, and is thus available to the erythron. There are however no in vitro data to support this hypothesis.
Safety issues also need to be considered when using intravenous iron, particularly as older preparations were associated with significant adverse events, including anaphylaxis. Recent pharmacological developments have led to the release of several new iron formulations including low molecular weight iron dextran (Cosmofer), iron sucrose (Venofer), ferric carboxymaltose (Ferinject) and sodium ferric gluconate (Ferrlecit). In the trials above, no excess of adverse effects was observed with these newer intravenous iron preparations. One hypothesis for the hypoferremia seen in ACD is that low iron levels might inhibit bacterial growth, as iron is essential for the growth and survival of intracellular bacteria, but there is no evidence to date that supplemental iron increases the risk of infections. However, the long-term effects of intravenous iron administration on other parameters, for example tumor growth and cardiovascular disease, have not been studied.
Saturday, August 13, 2011
Anemia of chronic disorders: the use of EPO
Erythropoiesis-stimulating agents
The reason for the use of erythropoiesis-stimulating agents like EPO in the anemia of chronic disorders (ACD) is the blunted response to EPO, with lower serum levels of EPO detected than would be expected for the observed degree of anemia, together with the reduced sensitivity of red cell progenitors to endogenous EPO seen in ACD. In addition, there are some data to suggest that the use of EPO may reverse the cytokine-mediated inhibition of red cell production.
Recombinant human EPO and its derivatives are widely used in patients with chronic renal failure, patients with cancer undergoing chemotherapy and patients infected with HIV on myelosuppressive anti-retroviral medication. Several different EPOs are currently available or in development: epoetin-alpha (Procrit, Epogen, Eprex), epoetin-β (NeoRecormon) epoetin-δ, biosimilar epoetins (Retacrit, Binocrit, Eporatio), darbepoietin-alpha (Aranesp), and continuous erythropoietin receptor activator (Mircera). In addition, a PEGylated synthetic dimeric peptide capable of binding to and stimulating the EPO receptor, Hematide, is undergoing clinical trials.
Much of the literature relating to the use of EPOs in ACD comes from renal medicine, but there is also evidence that these agents have useful activity in other forms of ACD, for example that seen in rheumatoid arthritis, HIV infection and cancer. Only relatively small studies of EPO usage have been performed in patients with ACD secondary to inflammatory conditions, for example a study by Pincus et al in which four of 13 patients treated with EPO at doses ranging from 50–150 iu/kg thrice weekly showed hematological responses, whereas none of four patients in the placebo arm responded. In another study, 34 patients with inflammatory bowel disease (IBD) refractory to iron therapy were randomly assigned to receive oral iron plus EPO or oral iron and placebo: after 12 weeks, Hb levels had increased by more than 10 g/l in 82% of the patients in the EPO group, as compared with 24% of those in the placebo group. However, the improvement in treatment of inflammatory conditions, such as rheumatoid arthritis or IBD, with anti-inflammatory and disease modifying agents, such as TNF-alpha inhibitors, with associated improvements in Hb levels, means that there is only a limited place for EPOs in their treatment.
There are many more studies of the use of EPO in patients with both solid tumour and hematological malignancies with response rates of 40–80% being seen. Many of these studies describe patients receiving anti-cancer treatment, so the anemia observed may be partly due to the myelosuppressive effects of chemotherapy or radiotherapy, rather than to the inflammatory effects of malignancy alone. However, early studies indicate that, although relative EPO deficiency contributes to the anemia of cancer in patients who are untreated, this effect is increased by the effects of chemotherapy.
Smith et al performed a dose- and schedule determining study in 188 patients with cancer not currently receiving chemotherapy, showing responses in the majority of patients. A recent large systematic review of 46 randomized controlled trials of ESA therapy in patients with cancer concluded that patients receiving EPO had a mean 16.3 g/l higher Hb level than controls, were 18% less likely to require blood transfusions, and had improved health-related quality of life, but survival benefits could not be established.
Responses may be reduced in ACD patients with more marked inflammation or where there is associated iron deficiency, especially in patients with IBD, highlighting both the importance of aiming treatment at the underlying condition and of ensuring replenishment of iron stores in patients who are iron deficient. As discussed previously, it may not always be easy to determine whether patients have ACD alone or ACD with iron deficiency, and evidence is accumulating that iron supplementation may be desirable in many patients treated with EPOs to ensure optimal response.
Predicting which patients with ACD will respond to exogenous EPO would be useful, but although various algorithms incorporating baseline endogenous EPO level, early response indicators and other factors, none of these will reliably predict response, at least in the setting of cancer-related anemia.
Warnings about the Dangers of EPOs
There has recently been mounting concern at possible detrimental effects of EPO administration in ACD, both in terms of cardiovascular risk and thrombosis, and relating to possible risks of tumour recurrence in patients with ACD related to malignancy. The CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) study showed that trying to achieve a target Hb level of 135 g/l (compared with 113 g/l) increased the risk of cardiovascular events and did not improve quality of life and the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy), demonstrated that patients with diabetes and chronic kidney disease were at greater risk of stroke following ESA administration and no clear benefit was observed. A randomized study of EPO in patients with non-small cell lung cancer (NSCLC) who were not receiving chemotherapy was terminated prematurely when a higher mortality rate was observed in the group receiving EPO.
These, and other, studies, together with suggestions that some tumour cells might express EPO receptors, raising the possibility that EPO might modulate tumour growth via cytoprotective effects, led the FDA in the United States to recommend that (i) prescribers should use the lowest dose of EPOs that would gradually increase Hb concentration to a level that would avoid the need for transfusion and (ii) treatment with EPOs might increase the risk of serious cardiovascular events and death when administered to produce Hb levels >120 g/l. In addition, the FDA recommends that (iii) EPOs should not be used in specific tumour types (breast, head and neck, NSCLC), nor be administered to patients with active malignancy not receiving chemo- or radiotherapy. Similar conclusions are reached in the updated guidelines published recently by ASH and ASCO.
However, a recent large meta-analysis of over 15,000 patients in 60 studies of EPOs in patients with cancer has shown no evidence that EPOs reduce survival or increase tumor progression in patients with cancer, although some increase in venous thrombembolism was observed. In addition, two recent studies have cast doubt on the idea that EPO receptors may be expressed at significant and clinically relevant levels on non-hematopoietic cells, including tumor cell lines, and it is clear that further, well-designed, clinical trials are necessary to define the role of EPOs in the anemia of malignancy. In the meantime, blood transfusion remains an option for treatment of anemia in patients with contraindicated cancers or those at high risk of venous thromboembolism.
The reason for the use of erythropoiesis-stimulating agents like EPO in the anemia of chronic disorders (ACD) is the blunted response to EPO, with lower serum levels of EPO detected than would be expected for the observed degree of anemia, together with the reduced sensitivity of red cell progenitors to endogenous EPO seen in ACD. In addition, there are some data to suggest that the use of EPO may reverse the cytokine-mediated inhibition of red cell production.
Recombinant human EPO and its derivatives are widely used in patients with chronic renal failure, patients with cancer undergoing chemotherapy and patients infected with HIV on myelosuppressive anti-retroviral medication. Several different EPOs are currently available or in development: epoetin-alpha (Procrit, Epogen, Eprex), epoetin-β (NeoRecormon) epoetin-δ, biosimilar epoetins (Retacrit, Binocrit, Eporatio), darbepoietin-alpha (Aranesp), and continuous erythropoietin receptor activator (Mircera). In addition, a PEGylated synthetic dimeric peptide capable of binding to and stimulating the EPO receptor, Hematide, is undergoing clinical trials.
Much of the literature relating to the use of EPOs in ACD comes from renal medicine, but there is also evidence that these agents have useful activity in other forms of ACD, for example that seen in rheumatoid arthritis, HIV infection and cancer. Only relatively small studies of EPO usage have been performed in patients with ACD secondary to inflammatory conditions, for example a study by Pincus et al in which four of 13 patients treated with EPO at doses ranging from 50–150 iu/kg thrice weekly showed hematological responses, whereas none of four patients in the placebo arm responded. In another study, 34 patients with inflammatory bowel disease (IBD) refractory to iron therapy were randomly assigned to receive oral iron plus EPO or oral iron and placebo: after 12 weeks, Hb levels had increased by more than 10 g/l in 82% of the patients in the EPO group, as compared with 24% of those in the placebo group. However, the improvement in treatment of inflammatory conditions, such as rheumatoid arthritis or IBD, with anti-inflammatory and disease modifying agents, such as TNF-alpha inhibitors, with associated improvements in Hb levels, means that there is only a limited place for EPOs in their treatment.
There are many more studies of the use of EPO in patients with both solid tumour and hematological malignancies with response rates of 40–80% being seen. Many of these studies describe patients receiving anti-cancer treatment, so the anemia observed may be partly due to the myelosuppressive effects of chemotherapy or radiotherapy, rather than to the inflammatory effects of malignancy alone. However, early studies indicate that, although relative EPO deficiency contributes to the anemia of cancer in patients who are untreated, this effect is increased by the effects of chemotherapy.
Smith et al performed a dose- and schedule determining study in 188 patients with cancer not currently receiving chemotherapy, showing responses in the majority of patients. A recent large systematic review of 46 randomized controlled trials of ESA therapy in patients with cancer concluded that patients receiving EPO had a mean 16.3 g/l higher Hb level than controls, were 18% less likely to require blood transfusions, and had improved health-related quality of life, but survival benefits could not be established.
Responses may be reduced in ACD patients with more marked inflammation or where there is associated iron deficiency, especially in patients with IBD, highlighting both the importance of aiming treatment at the underlying condition and of ensuring replenishment of iron stores in patients who are iron deficient. As discussed previously, it may not always be easy to determine whether patients have ACD alone or ACD with iron deficiency, and evidence is accumulating that iron supplementation may be desirable in many patients treated with EPOs to ensure optimal response.
Predicting which patients with ACD will respond to exogenous EPO would be useful, but although various algorithms incorporating baseline endogenous EPO level, early response indicators and other factors, none of these will reliably predict response, at least in the setting of cancer-related anemia.
Warnings about the Dangers of EPOs
There has recently been mounting concern at possible detrimental effects of EPO administration in ACD, both in terms of cardiovascular risk and thrombosis, and relating to possible risks of tumour recurrence in patients with ACD related to malignancy. The CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) study showed that trying to achieve a target Hb level of 135 g/l (compared with 113 g/l) increased the risk of cardiovascular events and did not improve quality of life and the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy), demonstrated that patients with diabetes and chronic kidney disease were at greater risk of stroke following ESA administration and no clear benefit was observed. A randomized study of EPO in patients with non-small cell lung cancer (NSCLC) who were not receiving chemotherapy was terminated prematurely when a higher mortality rate was observed in the group receiving EPO.
These, and other, studies, together with suggestions that some tumour cells might express EPO receptors, raising the possibility that EPO might modulate tumour growth via cytoprotective effects, led the FDA in the United States to recommend that (i) prescribers should use the lowest dose of EPOs that would gradually increase Hb concentration to a level that would avoid the need for transfusion and (ii) treatment with EPOs might increase the risk of serious cardiovascular events and death when administered to produce Hb levels >120 g/l. In addition, the FDA recommends that (iii) EPOs should not be used in specific tumour types (breast, head and neck, NSCLC), nor be administered to patients with active malignancy not receiving chemo- or radiotherapy. Similar conclusions are reached in the updated guidelines published recently by ASH and ASCO.
However, a recent large meta-analysis of over 15,000 patients in 60 studies of EPOs in patients with cancer has shown no evidence that EPOs reduce survival or increase tumor progression in patients with cancer, although some increase in venous thrombembolism was observed. In addition, two recent studies have cast doubt on the idea that EPO receptors may be expressed at significant and clinically relevant levels on non-hematopoietic cells, including tumor cell lines, and it is clear that further, well-designed, clinical trials are necessary to define the role of EPOs in the anemia of malignancy. In the meantime, blood transfusion remains an option for treatment of anemia in patients with contraindicated cancers or those at high risk of venous thromboembolism.
Friday, August 12, 2011
Treatment of the anemia of chronic disorder
The anemia observed in ACD is frequently mild, and correction may not always be necessary. There are, however, several reasons for attempting to correct the anemia present. First, anemia may be deleterious in itself, with effects on the cardiovascular system needed to maintain tissue oxygen supply. Second, anemia may be associated with a poorer prognosis in many chronic disease states, although whether anemia plays a causative role in determining prognosis is open to debate. Third, treatment may improve the quality of life for patients living with chronic conditions.
Treatment of the underlying inflammatory or malignant process associated with ACD will often result in improvement in the degree of anemia, examples being the use of corticosteroids in polymyalgia rheumatica, the use of TNF-alpha inhibitors in rheumatoid arthritis or inflammatory bowel disease, and the use of antiretroviral drugs in HIV infection. Indeed the severity of the anaemia will frequently mirror the activity of the chronic condition causing it, for example in rheumatoid arthritis. However, treatment of the underlying condition may not always be possible, for example in patients with incurable cancers or cardiac failure and alternative strategies may be necessary. Correction of as many contributory factors as possible is also desirable, for example correction of nutritional deficiencies.
Blood transfusion
Blood transfusion is widely available in the developed world and is a simple means of treating patients with moderate to severe anaemia, but blood remains a precious and expensive resource, and transfusion therapy carries long-term risks of viral transmission, iron overload and alloimmunization. Transfusion should therefore be reserved for patients with severe or life-threatening anaemia in the context of ACD, and is not an appropriate treatment for patients with this form of chronic anaemia.
Treatment of the underlying inflammatory or malignant process associated with ACD will often result in improvement in the degree of anemia, examples being the use of corticosteroids in polymyalgia rheumatica, the use of TNF-alpha inhibitors in rheumatoid arthritis or inflammatory bowel disease, and the use of antiretroviral drugs in HIV infection. Indeed the severity of the anaemia will frequently mirror the activity of the chronic condition causing it, for example in rheumatoid arthritis. However, treatment of the underlying condition may not always be possible, for example in patients with incurable cancers or cardiac failure and alternative strategies may be necessary. Correction of as many contributory factors as possible is also desirable, for example correction of nutritional deficiencies.
Blood transfusion
Blood transfusion is widely available in the developed world and is a simple means of treating patients with moderate to severe anaemia, but blood remains a precious and expensive resource, and transfusion therapy carries long-term risks of viral transmission, iron overload and alloimmunization. Transfusion should therefore be reserved for patients with severe or life-threatening anaemia in the context of ACD, and is not an appropriate treatment for patients with this form of chronic anaemia.
Thursday, August 11, 2011
Anemia of chronic disorders: Hepcidin levels
Hepcidin assays
The central role played by hepcidin in the pathogenesis of ACD suggests that measurement of hepcidin levels might be a useful diagnostic tool in the evaluation of possible ACD. The first measurements of hepcidin relied on extraction from urine, and were laborious, but more recently mass spectrometric and immunological methods to measure levels in urine and serum have been developed with potential for clinical use, and some are now commercially available.
Elevated serum hepcidin levels have been observed in a variety of inflammatory diseases, including rheumatological conditions, inflammatory bowel disease, infections, multiple myeloma, non-Hodgkin lymphoma and critical illness. However, whilst hepcidin levels will usually be elevated in these inflammatory anaemias, levels may not be elevated in patients who have co-existent ACD and iron deficiency as the inflammation-induced increase in hepcidin production will be opposed by the effects of iron deficiency: indeed the long-term effects of hepcidin may to be produce iron deficiency through reduced intestinal iron absorption, so the use of hepcidin levels to diagnose ACD will need to be evaluated carefully. Hepcidin levels may therefore be more useful in distinguishing patients with pure ACD from those with combined ACD and iron deficiency and this may be of therapeutic value. Further standardization and investigation is probably required before hepcidin levels come into routine and widespread clinical use however.
Whether the anaemia observed in some elderly patients has the same pathogenesis as ACD has been a subject of considerable debate. In a large study of patients aged 65 years and over, the relationships between urinary hepcidin, iron status, anaemia and inflammatory markers were investigated: surprisingly, urinary hepcidin levels were closely associated with markers of iron status but not with inflammatory markers, raising the possibility that hepcidin-independent pathways may contribute to hypoferraemia and anaemia in ACD, or that hepcidin levels may only be elevated in settings of overt inflammation.
Growth differentiation factor 15
Growth differentiation factor 15 (GDF15) is an erythropoiesis-derived hormone that is markedly increased in β-thalassaemia and congenital dyserythropoietic anaemia, and inhibits hepcidin expression, contributing to the iron overload seen in these anaemias. Levels of GDF15 have been studied in patients with ACD, ACD/IDA and IDA. Subjects with both ACD and ACD/IDA showed significantly higher levels of GDF15 than patients with IDA, and GDF15 concentrations correlated with interleukin-1β, suggesting that inflammation induces GDF15 expression, although the pathophysiological relevance of this is unclear.
The central role played by hepcidin in the pathogenesis of ACD suggests that measurement of hepcidin levels might be a useful diagnostic tool in the evaluation of possible ACD. The first measurements of hepcidin relied on extraction from urine, and were laborious, but more recently mass spectrometric and immunological methods to measure levels in urine and serum have been developed with potential for clinical use, and some are now commercially available.
Elevated serum hepcidin levels have been observed in a variety of inflammatory diseases, including rheumatological conditions, inflammatory bowel disease, infections, multiple myeloma, non-Hodgkin lymphoma and critical illness. However, whilst hepcidin levels will usually be elevated in these inflammatory anaemias, levels may not be elevated in patients who have co-existent ACD and iron deficiency as the inflammation-induced increase in hepcidin production will be opposed by the effects of iron deficiency: indeed the long-term effects of hepcidin may to be produce iron deficiency through reduced intestinal iron absorption, so the use of hepcidin levels to diagnose ACD will need to be evaluated carefully. Hepcidin levels may therefore be more useful in distinguishing patients with pure ACD from those with combined ACD and iron deficiency and this may be of therapeutic value. Further standardization and investigation is probably required before hepcidin levels come into routine and widespread clinical use however.
Whether the anaemia observed in some elderly patients has the same pathogenesis as ACD has been a subject of considerable debate. In a large study of patients aged 65 years and over, the relationships between urinary hepcidin, iron status, anaemia and inflammatory markers were investigated: surprisingly, urinary hepcidin levels were closely associated with markers of iron status but not with inflammatory markers, raising the possibility that hepcidin-independent pathways may contribute to hypoferraemia and anaemia in ACD, or that hepcidin levels may only be elevated in settings of overt inflammation.
Growth differentiation factor 15
Growth differentiation factor 15 (GDF15) is an erythropoiesis-derived hormone that is markedly increased in β-thalassaemia and congenital dyserythropoietic anaemia, and inhibits hepcidin expression, contributing to the iron overload seen in these anaemias. Levels of GDF15 have been studied in patients with ACD, ACD/IDA and IDA. Subjects with both ACD and ACD/IDA showed significantly higher levels of GDF15 than patients with IDA, and GDF15 concentrations correlated with interleukin-1β, suggesting that inflammation induces GDF15 expression, although the pathophysiological relevance of this is unclear.
Wednesday, August 10, 2011
ACD: differential diagnosis especially from iron deficiency
The diagnosis of ACD is not easy and the differential diagnosis is wide including hemoglobinopathies, nutritional deficiencies, bleeding or hemolysis, medications, recurrent phlebotomy, and bone marrow infection or infiltration. Typically the anemia is mild to moderate, and the textbooks say normochromic and normocytic (although anemia may become microcytic as disease progresses). I think this is wrong and put about by academics who haven't spent thousands of hours looking at blood films of medical patients as I have. In my experience the anemia is often hypochromic and microcytic, reflecting the unavailability of perfectly adequate irons stores, though I conceed that concomitant iron deficiency may also be present (these patients are often treated with NSAIDS that cause gastrointestinal bleeding).
The reticulocyte count is low, reflecting the hypoproliferative nature of the anemia. Inflammation may be inferred from other features of the blood count, such as neutrophilia, monocytosis or thrombocytosis, and through measurement of non-specific inflammatory markers, such as C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR).
Exclusion of iron deficiency anemia is very important in the work-up of patients with ACD, although the two conditions frequently co-exist. Typically, serum iron and transferrin saturation are both decreased in ACD, indicating limited iron supply to the red cells, but transferrin levels are increased in IDA, whereas in ACD they are normal or decreased. Measurement of serum ferritin is frequently of little value, as ferritin is an acute phase protein as well as an indicator of iron stores, and levels will be increased in the presence of inflammation. The gold standard for assessment of iron stores remains a Perl’s stained bone marrow aspirate, but a bone marrow biopsy is otherwise of limited value in the diagnosis of ACD, so other non-invasive tools for measurement of iron supply are needed.
Serum transferrin receptor (sTFR) and sTFR/ferritin ratio
The measurement of sTFR, the truncated fragment of the membrane receptor, has been suggested as a possible tool for differentiating between ACD and IDA. The transferrin receptor is found on virtually all cells in the body, but is present at high levels on erythroid progenitors. sTFR levels increase in IDA as the availability of iron for erythropoiesis decreases, whereas in ACD levels may not differ from steady state because transferrin receptor expression is negatively affected by inflammatory cytokines. However, in practice interpretation of this assay in differentiating IDA from ACD has proved more difficult, and the assay has not been standardized. In CLL sTFR gives false values and is not used.
The ratio of sTFR to the log of the serum ferritin has been proposed to be a useful tool in the diagnosis of ACD, and particularly in differentiating ACD from IDA. A ratio <1 makes ACD likely, whereas ratios >2 suggest that iron stores are deficient, with or without ACD.
Red cell indices
Many modern haematology analysers are capable of calculating new red cell indices that may be useful in the evaluation of different forms of anaemia. Two of these, the reticulocyte haemoglobin content (CHr) and the percentage hypochromic red cells (%HYPO) (reported by Bayer Advia 120 haematology analyser) can provide information about iron supply to the erythron, and may be useful in guiding the management of ACD. CHr is a measure of haemoglobin in the most recently formed erythrocytes, while the %HYPO indicates the percentage of cells with haemoglobin content of <280 g/l. The former gives a relatively acute evaluation (48 h) of recent bone marrow activity, whereas the latter gives a time-averaged picture (20–120 d). Similar indices can be reported by the Sysmex XE-2100 analyser), which derives RET-Y (equivalent to CHr) and RBC-Y (equivalent to HYPO%). CHr has been shown to be a useful tool in the detection of early iron deficiency, as well as in monitoring early response to iron therapy.
A study has been made of the relationship between CHr, %HYPO and sTFR/ferritin ratio to evaluate anaemia in 442 patients with disease-specific anaemias and 154 non-anaemic subjects. A simple plot of CHr against sTFR/ferritin divided anaemic samples into four functional quadrants: (i) iron replete, normal eythropoiesis; (ii) reduced iron supply but not yet iron-deficient erythropoiesis; (iii) iron depleted with iron-deficient erythropoiesis; (iv) iron replete but with functional iron deficiency leading to decreased haemoglobinization. This may help in deciding whether iron supplementation may improve haemoglobin levels in individual patients. It is not known whether this will be valid in CLL patients.
The reticulocyte count is low, reflecting the hypoproliferative nature of the anemia. Inflammation may be inferred from other features of the blood count, such as neutrophilia, monocytosis or thrombocytosis, and through measurement of non-specific inflammatory markers, such as C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR).
Exclusion of iron deficiency anemia is very important in the work-up of patients with ACD, although the two conditions frequently co-exist. Typically, serum iron and transferrin saturation are both decreased in ACD, indicating limited iron supply to the red cells, but transferrin levels are increased in IDA, whereas in ACD they are normal or decreased. Measurement of serum ferritin is frequently of little value, as ferritin is an acute phase protein as well as an indicator of iron stores, and levels will be increased in the presence of inflammation. The gold standard for assessment of iron stores remains a Perl’s stained bone marrow aspirate, but a bone marrow biopsy is otherwise of limited value in the diagnosis of ACD, so other non-invasive tools for measurement of iron supply are needed.
Serum transferrin receptor (sTFR) and sTFR/ferritin ratio
The measurement of sTFR, the truncated fragment of the membrane receptor, has been suggested as a possible tool for differentiating between ACD and IDA. The transferrin receptor is found on virtually all cells in the body, but is present at high levels on erythroid progenitors. sTFR levels increase in IDA as the availability of iron for erythropoiesis decreases, whereas in ACD levels may not differ from steady state because transferrin receptor expression is negatively affected by inflammatory cytokines. However, in practice interpretation of this assay in differentiating IDA from ACD has proved more difficult, and the assay has not been standardized. In CLL sTFR gives false values and is not used.
The ratio of sTFR to the log of the serum ferritin has been proposed to be a useful tool in the diagnosis of ACD, and particularly in differentiating ACD from IDA. A ratio <1 makes ACD likely, whereas ratios >2 suggest that iron stores are deficient, with or without ACD.
Red cell indices
Many modern haematology analysers are capable of calculating new red cell indices that may be useful in the evaluation of different forms of anaemia. Two of these, the reticulocyte haemoglobin content (CHr) and the percentage hypochromic red cells (%HYPO) (reported by Bayer Advia 120 haematology analyser) can provide information about iron supply to the erythron, and may be useful in guiding the management of ACD. CHr is a measure of haemoglobin in the most recently formed erythrocytes, while the %HYPO indicates the percentage of cells with haemoglobin content of <280 g/l. The former gives a relatively acute evaluation (48 h) of recent bone marrow activity, whereas the latter gives a time-averaged picture (20–120 d). Similar indices can be reported by the Sysmex XE-2100 analyser), which derives RET-Y (equivalent to CHr) and RBC-Y (equivalent to HYPO%). CHr has been shown to be a useful tool in the detection of early iron deficiency, as well as in monitoring early response to iron therapy.
A study has been made of the relationship between CHr, %HYPO and sTFR/ferritin ratio to evaluate anaemia in 442 patients with disease-specific anaemias and 154 non-anaemic subjects. A simple plot of CHr against sTFR/ferritin divided anaemic samples into four functional quadrants: (i) iron replete, normal eythropoiesis; (ii) reduced iron supply but not yet iron-deficient erythropoiesis; (iii) iron depleted with iron-deficient erythropoiesis; (iv) iron replete but with functional iron deficiency leading to decreased haemoglobinization. This may help in deciding whether iron supplementation may improve haemoglobin levels in individual patients. It is not known whether this will be valid in CLL patients.
Anemia of chronic disorders: is red cell lifespan shortened?
Reduced red cell survival
Early studies (from 1966) suggested that red cell survival is shortened in ACD and more recent research using breath carbon monoxide levels to assess red cell survival confirms that red cell survival is modestly shortened in patients with rheumatoid arthritis and anemic hospital inpatients. This may be a contributory factor in ACD, but there have been no direct studies of the mechanisms involved. These might include increased erythrophagocytosis induced by inflammatory cytokines or oxidative damage to erythrocytes, causing reduced survival.
Early studies (from 1966) suggested that red cell survival is shortened in ACD and more recent research using breath carbon monoxide levels to assess red cell survival confirms that red cell survival is modestly shortened in patients with rheumatoid arthritis and anemic hospital inpatients. This may be a contributory factor in ACD, but there have been no direct studies of the mechanisms involved. These might include increased erythrophagocytosis induced by inflammatory cytokines or oxidative damage to erythrocytes, causing reduced survival.
Tuesday, August 09, 2011
Anemia of chronic disorders: the effect of EPO
Reduced EPO production
Under normal physiological conditions, levels of EPO are inversely correlated with hemoglobin levels and tissue oxygenation, but in chronic inflammatory conditions the EPO response is blunted, leading to inadequate levels of EPO for the degree of anemia, and this is thought to be mediated via inflammatory cytokines such as IL-1 and TNF-alpha, though not all studies confirm this.
Reduced erythroid responsiveness
In ACD, the proliferation and differentiation of erythroid progenitor cells is reduced. Early studies showed that macrophages from patients with ACD could suppress erythroid colony formation in vitro. Subsequent studies showed this effect to be due to inhibitory effects of inflammatory cytokines, especially interferon-gamma, on growth of BFU-E and CFU-E, and that this effect could be overcome by addition of high concentrations of EPO to the culture systems. Hepcidin itself has an inhibitory effect on erythropoiesis in vitro at low EPO concentrations.
It has been demonstrated that bone marrow cultures from patients with active rheumatoid arthritis showed defective growth when compared to normal controls, and that there was an inverse correlation between colony growth and levels of TNF-alpha in the culture supernatant. Moreover, these effects were reversed both in vitro and in vivo following treatment with infliximab, an antibody against TNF-alpha.
Under normal physiological conditions, levels of EPO are inversely correlated with hemoglobin levels and tissue oxygenation, but in chronic inflammatory conditions the EPO response is blunted, leading to inadequate levels of EPO for the degree of anemia, and this is thought to be mediated via inflammatory cytokines such as IL-1 and TNF-alpha, though not all studies confirm this.
Reduced erythroid responsiveness
In ACD, the proliferation and differentiation of erythroid progenitor cells is reduced. Early studies showed that macrophages from patients with ACD could suppress erythroid colony formation in vitro. Subsequent studies showed this effect to be due to inhibitory effects of inflammatory cytokines, especially interferon-gamma, on growth of BFU-E and CFU-E, and that this effect could be overcome by addition of high concentrations of EPO to the culture systems. Hepcidin itself has an inhibitory effect on erythropoiesis in vitro at low EPO concentrations.
It has been demonstrated that bone marrow cultures from patients with active rheumatoid arthritis showed defective growth when compared to normal controls, and that there was an inverse correlation between colony growth and levels of TNF-alpha in the culture supernatant. Moreover, these effects were reversed both in vitro and in vivo following treatment with infliximab, an antibody against TNF-alpha.
Monday, August 08, 2011
Anemia of chronic disorders: Hepcidin
Altered iron homeostasis
Low serum iron levels are a common feature of ACD: mice injected with pro-inflammatory cytokines, IL-1 and TNF-alpha developed low serum irons and anemia and in human volunteers, injection of IL-6 caused reduction in serum iron levels and transferrin saturation, This effect is now known to be mediated via a 25 amino acid polypeptide hormone known as hepcidin.
Hepcidin is produced by liver cells (and to a lesser extent fat cells and macrophages) and plays a key role in the regulation of iron balance and transport. The hormone’s actions work through its binding to ferroportin, the major protein for removing iron from cells, resulting in the blockade of iron export from body iron stores in macrophages and liver cells; Also inhibition of iron absorption by the duodenum occurs, although recent evidence suggests that this may be caused by downregulation of another transport protein, divalent metal transporter-1 (DMT-1) rather than ferroportin. The combined effect is to restrict iron availability for erythropoiesis, sometimes referred to as a state of ‘functional iron deficiency’, (which is why ACD is often microcytic rather than normocytic as most of the text books assert, and to result in iron accumulation in tissue macrophages. Hepcidin overexpression in transgenic mice reproduces many of the features of ACD and hepcidin levels are raised in a variety of inflammatory disorders. Once bound to ferroportin, the ligand-receptor complex is internalized and degraded, and cellular iron export ceases.
Normally, regulation of hepcidin production occurs through recognition of iron levels and erythropoietic activity. Thus iron excess stimulates hepcidin production, leading to reduced iron absorption and switching off iron release from tissue stores. Conversely, in iron deficiency, hepcidin production is suppressed, enabling increased iron absorption and release of storage iron: similar changes occur when erythroid activity increases.
In inflammatory conditions, hepcidin production is increased, and IL-6 has been shown to be a potent inducer of hepcidin via STAT-3signaling. There is also evidence of a role for other inflammatory cytokines, including IL-1 and bone morphogenetic proteins (BMPs) 2, 4, 6 and 9.
Parallel processes can be seen in malignant conditions. For example, in patients with Hodgkin lymphoma, hepcidin levels were closely correlated with levels of IL-6, rather than other cytokines whereas a recent study suggests that BMP-2, rather than IL-6, is the key inducer of hepcidin in patients with multiple myeloma: hepcidin levels in patients with myeloma inversely correlate with hemoglobin levels, and anti-BMP-2 antibodies blocked the hepcidin-inducing activity of sera from patients with myeloma more consistently than anti-IL-6.
That the erythropoietic and inflammatory pathways regulating hepcidin production may be separate was suggested by a recent study: using a rat model of ACD, it demonstrated that animals with ACD rendered iron-deficient by phlebotomy had lower hepcidin levels than animals with ACD alone. Similar findings were noted in patients with ACD/IDA when compared to individuals with ACD, and the former were able to absorb dietary iron and mobilize iron from macrophage stores. This is an important observation if hepcidin levels are to be incorporated into the diagnostic pathway for patients with ACD.
Low serum iron levels are a common feature of ACD: mice injected with pro-inflammatory cytokines, IL-1 and TNF-alpha developed low serum irons and anemia and in human volunteers, injection of IL-6 caused reduction in serum iron levels and transferrin saturation, This effect is now known to be mediated via a 25 amino acid polypeptide hormone known as hepcidin.
Hepcidin is produced by liver cells (and to a lesser extent fat cells and macrophages) and plays a key role in the regulation of iron balance and transport. The hormone’s actions work through its binding to ferroportin, the major protein for removing iron from cells, resulting in the blockade of iron export from body iron stores in macrophages and liver cells; Also inhibition of iron absorption by the duodenum occurs, although recent evidence suggests that this may be caused by downregulation of another transport protein, divalent metal transporter-1 (DMT-1) rather than ferroportin. The combined effect is to restrict iron availability for erythropoiesis, sometimes referred to as a state of ‘functional iron deficiency’, (which is why ACD is often microcytic rather than normocytic as most of the text books assert, and to result in iron accumulation in tissue macrophages. Hepcidin overexpression in transgenic mice reproduces many of the features of ACD and hepcidin levels are raised in a variety of inflammatory disorders. Once bound to ferroportin, the ligand-receptor complex is internalized and degraded, and cellular iron export ceases.
Normally, regulation of hepcidin production occurs through recognition of iron levels and erythropoietic activity. Thus iron excess stimulates hepcidin production, leading to reduced iron absorption and switching off iron release from tissue stores. Conversely, in iron deficiency, hepcidin production is suppressed, enabling increased iron absorption and release of storage iron: similar changes occur when erythroid activity increases.
In inflammatory conditions, hepcidin production is increased, and IL-6 has been shown to be a potent inducer of hepcidin via STAT-3signaling. There is also evidence of a role for other inflammatory cytokines, including IL-1 and bone morphogenetic proteins (BMPs) 2, 4, 6 and 9.
Parallel processes can be seen in malignant conditions. For example, in patients with Hodgkin lymphoma, hepcidin levels were closely correlated with levels of IL-6, rather than other cytokines whereas a recent study suggests that BMP-2, rather than IL-6, is the key inducer of hepcidin in patients with multiple myeloma: hepcidin levels in patients with myeloma inversely correlate with hemoglobin levels, and anti-BMP-2 antibodies blocked the hepcidin-inducing activity of sera from patients with myeloma more consistently than anti-IL-6.
That the erythropoietic and inflammatory pathways regulating hepcidin production may be separate was suggested by a recent study: using a rat model of ACD, it demonstrated that animals with ACD rendered iron-deficient by phlebotomy had lower hepcidin levels than animals with ACD alone. Similar findings were noted in patients with ACD/IDA when compared to individuals with ACD, and the former were able to absorb dietary iron and mobilize iron from macrophage stores. This is an important observation if hepcidin levels are to be incorporated into the diagnostic pathway for patients with ACD.
Sunday, August 07, 2011
The anemia of chronic disorders
When I was working at Bournemouth, one of my Wessex colleagues was Salisbury consultant haematologist Jonathan Cullis. He was an ex registrar from the Hammersmith hospital who had been there with my buddy, David Oscier. He has produced an excellent review of the anemia of chronic disease, which is obviously relevant for CLL sufferers so I am going to review this paper, step by step as a service to them.
Anemia of chronic disease (ACD), or anemia of inflammation, is the term used to describe the anemia with reduced red cell production seen in response to systemic illness or inflammation. It is the second most prevalent form of anemia after iron deficiency anemia (IDA) and the most common amongst patients with chronic illnesses. It is seen in a variety of conditions, including infections, cancer and autoimmune conditions. The anemia of chronic renal failure, although sometimes referred to as ACD, should not be included and will only be discussed to throw insights into other forms of ACD can be derived from relevant papers. ACD is typically normochromic and normocytic (but often microcytic), characterized by low serum iron, decreased transferrin saturation, decreased bone marrow sideroblasts and increased reticuloendothelial iron. The mechanisms that produce the anemia include impaired production of erythropoietin (EPO), blunted marrow erythroid response to EPO, iron-restricted erythropoiesis, and a diminished pool of EPO-responsive cells.
Among the conditions associated with ACD are viral, bacterial, parasitic and fungal infections, hematological and solid tumor malignancies, autoimmune conditions like rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, vasculitis, polymyalgia, systemic sclerosis, polymyositis, sarcoidosis and inflammatory bowel disease, and some cardiac diseases such as chronic heart failure.
Anemia of chronic disease (ACD), or anemia of inflammation, is the term used to describe the anemia with reduced red cell production seen in response to systemic illness or inflammation. It is the second most prevalent form of anemia after iron deficiency anemia (IDA) and the most common amongst patients with chronic illnesses. It is seen in a variety of conditions, including infections, cancer and autoimmune conditions. The anemia of chronic renal failure, although sometimes referred to as ACD, should not be included and will only be discussed to throw insights into other forms of ACD can be derived from relevant papers. ACD is typically normochromic and normocytic (but often microcytic), characterized by low serum iron, decreased transferrin saturation, decreased bone marrow sideroblasts and increased reticuloendothelial iron. The mechanisms that produce the anemia include impaired production of erythropoietin (EPO), blunted marrow erythroid response to EPO, iron-restricted erythropoiesis, and a diminished pool of EPO-responsive cells.
Among the conditions associated with ACD are viral, bacterial, parasitic and fungal infections, hematological and solid tumor malignancies, autoimmune conditions like rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, vasculitis, polymyalgia, systemic sclerosis, polymyositis, sarcoidosis and inflammatory bowel disease, and some cardiac diseases such as chronic heart failure.
Monday, August 23, 2010
Iron deficiency in CLL
I am grateful to correspondent,Lynn, for drawing attention to something that had passed me by while I was ill. In distinguishing between iron deficiency and the anemia of chronic disorders, it is usually sufficient to measure the serum iron, the total iron binding capacity and the serum ferritin. In both, the serum iron will be low, but the iron binding capacity goes up in iron deficiency and down in the anemia of chronic disorders. Serum ferritin goes down in iron deficiency and is normal or raised in chronic disorders.
Sometimes patients have both iron deficiency and a chronic disorder, so how do you decide whether they should be given iron?
A few years ago the serum soluble transferrin receptor assay became available. This goes up in iron deficiency but is unaffected by chronic disorders.
However, this is not true for some hematological malignancies, especially for CLL. The serum soluble transferrin receptor level goes up in CLL and indeed is a measurement of tumor burden. So if you really are not sure whether someone with CLL is also iron deficient and the other tests won't help you, then the only way to find out for sure is to do a bone marrow biopsy and stain it for iron.
Sometimes patients have both iron deficiency and a chronic disorder, so how do you decide whether they should be given iron?
A few years ago the serum soluble transferrin receptor assay became available. This goes up in iron deficiency but is unaffected by chronic disorders.
However, this is not true for some hematological malignancies, especially for CLL. The serum soluble transferrin receptor level goes up in CLL and indeed is a measurement of tumor burden. So if you really are not sure whether someone with CLL is also iron deficient and the other tests won't help you, then the only way to find out for sure is to do a bone marrow biopsy and stain it for iron.
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