Anemia Of Chronic Disease Patients Research Articles

Iron Deficiency Anemia Diagnosed in the Private Practice Setting,

Abstract 3186▪▪This icon denotes a clinically relevant abstract Introduction:Iron deficiency anemia (IDA) continues to be a problem in the United States in the 21st Century. Differentiating IDA from anemia of chronic disease (ACD) is important in the clinical practice setting because iron supplementation has been shown to be beneficial for IDA and may deleteriously affect ACD patients. We examined consecutive patients referred for a diagnosis of anemia in a single community-based hematology-oncology practice in the suburbs of a major city over an 8 month period. IDA was found amongst these patients. The common possible causes, symptoms and usual treatment for this subset of patients are reported. Methods:Records of all adult patients referred to the practice with a diagnosis of anemia and were then confirmed to be iron deficiency anemia from March 2010 until November 2010 were reviewed. Chart review analysis was performed to identify differences in gender, causes, symptoms, treatment plans, treatment efficacy, pertinent history and physical findings including laboratory studies - CBC, ferritin, iron/TIBC, reticulocyte count, review of the peripheral blood film, and often but not always, an erythropoietin level. Results:A significant number of patients (n = 130) demonstrated iron deficiency anemia. The vast majority of these patients were female (94%). Most patients were also premenopausal. Four patients were pregnant. The most common cause of iron deficiency anemia was heavy menstrual blood loss associated with the presence of uterine fibroids (67%) followed by, gastric bypass surgery (24%). Interestingly, a subset of patients (12%) had a history of both gastric bypass and heavy menstrual blood loss. Other associated causes found to be linked to IDA were gastrointestinal lesions, such as AV malformations, gastritis, including medication induced gastritis (nonsteroidal anti-inflammatory drugs), hiatal hernia and at least one colon cancer. Subjective symptoms of IDA included tiredness, weakness, exhaustion, brittle nails and hair loss. The finding of pica was quite extensive and often not reported by the patient unless questioned in detail. Pica symptoms included the desire for ice (pagophagia), clay or starch, and also revealed some unusual urges, including eating toilet paper or paper towels, dirt from a patient's rose garden, or the urge to chew gum with the amount exceeding several packages of greater than 10 sticks each per day. One patient reported eating leaves which were stripped from a garden plant. Laboratory studies on these patient subset revealed only 3 had a ferritin level greater than 20 ng/mL (3%). The MCV was less than 80 fl in 111 of the 130 patients. Thrombocytosis (a platelet count of greater than 400,000.103 ml) was an associated finding of IDA and occurred 40 of 130 patients (30%). The platelet count returned to normal in all but one patient post treatment. Conclusion:Iron deficiency is a pervasive problem that is not adequately assessed and treated. Many of our clinic patients developed iron deficiency anemia as a result of surgical intervention, such as gastric bypass surgery. We recommend identifying IDA early to treat patients efficaciously for optimal outcomes. Close attention should be given to key clinical indicators including low MCV and variant forms of pica syndrome which is a valid symptom of iron deficiency. Our experience with administering intravenous iron preparations suggests that patients have improvements in overall well being often within a few days of the first infusion. The pica syndrome resolved in approximately two weeks post the first dose of iron in most patients, even prior to demonstrating any significant improvement in the hemoglobin and hematocrit or the MCV levels. This may imply that iron deficiency affects fundamental enzymes for metabolic processes found in the oral mucosa leading to the PICA.Intravenous iron administration was often used in our practice to bring the hemoglobin and hematocrit to more favorable levels in order to reduce symptoms of iron deficiency or to undergo surgical procedures and childbirth as needed. There was an occasional reaction to intravenous iron that included pruritis, back pain and an unusual swelling in the joints (e.g., knees). We have treated these patients with 100 mg of hydrocortisone intravenously and 25 mg of diphenhydramine intravenously. All reactions usually abated within 30 minutes. We had no fatal reactions to the use of intravenous iron preparations. Disclosures:No relevant conflicts of interest to declare.

The diagnostic accuracy of the percentage of hypochromic red blood cells (%HYPOm) and cellular hemoglobin in reticulocytes (CHr) in differentiating iron deficiency anemia and anemia of chronic diseases

BackgroundThe percentages of hypochromic red blood cells (%HYPOm) and cellular hemoglobin in reticulocytes (CHr) are suggested to be useful screening markers of iron deficiency. The aim of this study was to investigate the diagnostic accuracy of %HYPOm and CHr in differentiating iron deficiency anemia (IDA) and anemia of chronic disease (ACD). MethodsThe retrospective population consisted of 58 IDA patients, 129 ACD patients and 63 controls, on whom bone marrow examination and blood count with %HYPOm and CHr had been performed. Receiver operating characteristic (ROC) analyses with area under the ROC curves (AUC) were used as statistical tests. ResultsAUCs for differentiating the groups using %HYPOm were as follows: IDA vs. controls 0.99, ACD vs. controls 0.85 and IDA vs. ACD 0.88. AUCs for CHr in distinguishing the groups were as follows: IDA vs. controls 0.95, ACD vs. controls 0.65 and IDA vs. ACD 0.83. ConclusionsIDA and ACD patients were efficiently differentiated by using %HYPOm and CHr. Additionally, %HYPOm was higher and CHr was lower in IDA patients and in ACD patients than in controls. Thus, %HYPOm is higher and CHr is lower not only in absolute iron deficiency, but also when iron availability for erythropoiesis is restricted.

Hepcidin expression in anemia of chronic disease and concomitant iron-deficiency anemia

Hepcidin is a key hormone governing mammalian iron homeostasis and may be directly or indirectly involved in the development of most iron deficiency/overload and inflammation-induced anemia. The objective of this study was to investigate the expression of hepcidin in anemia of chronic disease. To characterize serum hepcidin, iron and inflammatory indicators associated with anemia of chronic disease (ACD), we studied ACD, ACD concomitant iron-deficiency anemia (ACD/IDA), pure IDA and acute inflammation (AcI) patients and analyzed the associations between hepcidin levels and inflammation parameters in various types of anemia. Serum hepcidin levels in patient groups were statistically different, from high to low: ACD, AcI > ACD/IDA > the control > IDA. Serum ferritin levels were significantly increased in ACD and AcI patients but were decreased significantly in ACD/IDA and IDA. Elevated serum EPO concentrations were found in ACD, ACD/IDA and IDA patients but not in AcI patients and the controls. A positive correlation between hepcidin and IL-6 levels only existed in ACD/IDA, AcI and the control groups. A positive correlation between hepcidin and ferritin was marked in the control group, while a negative correlation between hepcidin and ferritin was noted in IDA. The significant negative correlation between hepcidin expression and reticulocyte count was marked in both ACD/IDA and IDA groups. All of these data demonstrated that hepcidin might play role in pathogenesis of ACD, ACD/IDA and IDA, and it could be a potential marker for detection and differentiation of these anemias.

Growth differentiation factor 15 in anaemia of chronic disease, iron deficiency anaemia and mixed type anaemia

Recently, the iron and erythropoiesis-controlled growth differentiation factor 15 (GDF15) has been shown to inhibit the expression of hepcidin in beta-thalassaemia patients, thereby increasing iron absorption despite iron overload. To access the diagnostic and pathogenic impact of GDF15 in inflammatory anaemia the association of GDF15 expression with serum iron parameters and hepcidin was studied in patients suffering from iron deficiency anaemia (IDA), anaemia of chronic disease (ACD) and ACD subjects with true iron deficiency (ACD/IDA). GDF15 was significantly increased in both ACD and ACD/IDA, but not in IDA subjects as compared to controls. In contrast, hepcidin levels were significantly lower in IDA and ACD/IDA subjects than in ACD patients. IDA and ACD/IDA, but not ACD, showed an association between GDF15 and soluble transferrin receptor, an indicator of iron requirement for erythropoiesis. However, GDF15 did not correlate to hepcidin in either patient group. While GDF15 levels were linked to the needs for erythropoiesis and iron homeostasis in IDA, the immunity-driven increase of GDF15 may not primarily affect iron homeostasis and hepcidin expression. This indicates that other ACD-related factors may overcome the regulatory effects of GDF15 on hepcidin expression during inflammation.

Autocrine formation of hepcidin induces iron retention in human monocytes

Hepcidin, a master regulator of iron homeostasis, is produced in small amounts by inflammatory monocytes/macrophages. Chronic immune activation leads to iron retention within monocytes/macrophages and the development of anemia of chronic disease (ACD). We questioned whether monocyte-derived hepcidin exerts autocrine regulation toward cellular iron metabolism. Monocyte hepcidin mRNA expression was significantly induced within 3 hours after stimulation with LPS or IL-6, and hepcidin mRNA expression was significantly higher in monocytes of ACD patients than in controls. In ACD patients, monocyte hepcidin mRNA levels were significantly correlated to serum IL-6 concentrations, and increased monocyte hepcidin mRNA levels were associated with decreased expression of the iron exporter ferroportin and iron retention in these cells. Transient transfection experiments using a ferroportin/EmGFP fusion protein construct demonstrated that LPS inducible hepcidin expression in THP-1 monocytes resulted in internalization and degradation of ferroportin. Transfection of monocytes with siRNA directed against hepcidin almost fully reversed this lipopolysaccharide-mediated effect. Using ferroportin mutation constructs, we found that ferroportin is mainly targeted by hepcidin when expressed on the cell surface. Our results suggest that ferroportin expression in inflammatory monocytes is negatively affected by autocrine formation of hepcidin, thus contributing to iron sequestration within monocytes as found in ACD.

Dysregulated monocyte iron homeostasis and erythropoietin formation in patients with anemia of chronic disease

Anemia of chronic disease (ACD) is frequently found in patients with chronic immune activation. Since most studies on ACD pathophysiology were performed with cell culture or animal models but not in humans, we examined 37 ACD patients suffering from autoimmune diseases or infections, 10 subjects with iron-deficiency anemia (IDA), 10 anemic patients with hereditary spherocytosis (HS), and 27 age-matched controls. Although hemoglobin concentrations were comparable between ACD and IDA patients, the latter presented with significantly higher serum erythropoietin concentrations than ACD patients. The significant negative correlation between erythropoietin and hemoglobin levels observed in IDA patients was also found in a group of anemic but not hypoferremic hereditary spherocytosis subjects, but not in ACD patients. Increased serum concentrations of the hepcidin precursor prohepcidin were paralleled by a decreased expression of the iron exporter ferroportin in circulating monocytes of ACD patients. In the latter cells, increased amounts of the iron storage protein ferritin and a reduced activity of iron-regulatory protein indicated monocyte iron accumulation. Our data indicate that hypoferremia in ACD may result from downregulation of ferroportin expression by hepcidin and cytokines with subsequent iron retention in monocytes. Together with a diminished erythropoietin formation, the impaired iron recirculation from monocytes may be central in the pathophysiology of ACD in humans.

Effects of Hepcidin, Ferritin, and Iron Deprivation on Erythroid Colony Formation in Vitro.

The anemia of chronic disease (ACD) results from a combination of three pathologic processes. In ACD, a modest shortening of red cell survival creates an increased demand for red cell production, which is not met because of an impaired erythropoietic response and defects in reticuloendothelial iron mobilization and utilization. The impaired erythropoietic response, in turn, has two components: a blunted erythropoietin response, and an impaired response of erythroid progenitors to erythropoietin. Recombinant human erythropoietin (rhEPO) can reverse this impaired progenitor response in vitro, and can also correct ACD in patients. These processes have generally been considered effects of the cytokines which mediate the immune and inflammatory response, such as tumor necrosis factor, interleukin-1, and the interferons. It has recently been proposed that hepcidin, a mediator of innate immunity with the iron regulatory properties, is the factor responsible for ACD. If this is the case, then hepcidin should be able to induce the pathophysiologic mechanisms implicated in ACD. We therefore evaluated the effects of hepcidin and associated phenomena on human CFU-E colony formation in vitro. All CFU-E cultures were performed in plasma clots in serum-containing medium with rhEPO 1 U/mL. Hepcidin at concentrations 10 ng/mL -10 μg/mL had no effect on CFU-E colony formation. A number of studies have demonstrated that increased hepcidin message expression and protein production are strongly associated with increases in serum ferritin concentrations, and so the effect of added ferritin on erythroid colony formation was studied. Neither ferritin nor apo-ferritin 10 – 1000 ng/mL had inhibitory effects on CFU-E colony formation. The effect of iron deprivation on erythroid colony formation was evaluated with using desferrioxamine. Desferrioxamine 0.01mM decreased CFU-E colony formation to 60% of control values, while higher concentrations completely ablated colony growth. In summary, hepcidin does not appear to inhibit CFU-E colony formation directly or indirectly through ferritin. It may exert such an effect by decreasing availability of iron for erythropoiesis; however, such a finding would be difficult to reconcile with the observed clinical response of ACD to rhEPO, given that iron availability is typically a limiting factor in the erythropoietic response to rhEPO. The role of hepcidin in the overall pathogenesis of ACD remains to be fully determined.

Serum transferrin receptor assay in iron deficiency anaemia and anaemia of chronic disease in the elderly.

The most common cause of anaemia in the elderly is anaemia of chronic disease (ACD). However, iron deficiency anaemia (IDA) may coexist, and can be difficult to diagnose. The serum transferrin receptor (sTfR) blood test may be a better indicator of iron status as it is not affected by inflammation nor by advancing age. We evaluated it in four groups (10 males, 10 females each): 'young' controls, 'elderly' controls, IDA and ACD. All patients in the IDA group had elevated sTfR levels (mean +/- SD 65.2 +/- 17.7 nmol/l). All 'young' controls had normal sTfR (22.3 +/- 7.3 nmol/l) and ferritin levels (92.7 +/- 61.1 micrograms/l). Although all subjects in the 'elderly' controls and ACD group had normal, and raised or normal serum ferritin, respectively (88 +/- 62.3 micrograms/l; 631.2 +/- 509.5 micrograms/l), three (15%) 'elderly' controls and four (20%) ACD patients had raised sTfR levels, suggesting depleted iron stores. Bone-marrow aspirates were available in 3/4 ACD patients with raised sTfR. Haemosiderin was absent in two. The sTfR blood test is comparable to serum ferritin in diagnosing IDA in the elderly but also seems capable of differentiating ACD from IDA. Its potential as a non-invasive test of iron status, especially in elderly anaemic patients, deserves further evaluation.

Serum Transferrin Receptor and Its Ratio to Serum Ferritin in the Diagnosis of Iron Deficiency

AbstractThe objective of the study was to evaluate the diagnostic efficiency of laboratory tests, including serum transferrin receptor (TfR) measurements, in the diagnosis of iron depletion. The patient population consisted of 129 consecutive anemic patients at the University Hospital of Turku who were given a bone marrow examination. Of these patients, 48 had iron deficiency anemia (IDA), 64 anemia of chronic disease (ACD), and 17 patients had depleted iron stores and an infectious or an inflammatory condition (COMBI). Depletion of iron stores was defined as a complete absence of stainable iron in the bone marrow examination. Serum TfR concentrations were elevated in the vast majority of the IDA and COMBI patients, while in the ACD patients, the levels were within the reference limits reported earlier for healthy subjects. TfR measurement thus provided a reliable diagnosis of iron deficiency anemia (AUCROC 0.98). Serum ferritin measurement also distinguished between IDA patients and ACD patients. However, the optimal decision limit for evaluation of ferritin measurements was considerably above the conventional lower reference limits, complicating the interpretation of this parameter. Calculation of the ratio TfR/log ferritin (TfR-F Index) is a way of combining TfR and ferritin results. This ratio provided an outstanding parameter for the identification of patients with depleted iron stores (AUCROC 1.00). In anemic patients, TfR measurement is a valuable noninvasive tool for the diagnosis of iron depletion, and offers an attractive alternative to more conventional laboratory tests in the detection of depleted iron stores.

Elevated serum transcobalamin levels in anaemia of rheumatoid arthritis: correlation with disease activity but not with serum tumour necrosis factor alpha and interleukin 6.

Transcobalamin (TCII) and haptocorrins (TCI and III), tumour necrosis factor alpha (TNF), interleukin-6 (IL6) and parameters of disease activity were assessed in 20 rheumatoid arthritis (RA) patients without anaemia and 19 subjects with anaemia of chronic disease (ACD) in order to determine if there was a possible correlation between these parameters. TCII, TNF and IL6 correlated positively with RA disease activity parameters, whereas their serum levels were higher in the ACD patients. TC levels were not correlated with cytokine levels. Vitamin B12 serum levels were lower in ACD. We conclude that in RA, elevated serum TCII levels are possibly mediated by increased RA disease activity, but probably not by actions of TNF or IL6. Increased TCII levels found in ACD may be explained by the higher degree of RA activity in these patients, and could also be viewed as a compensatory reaction to anaemia or reduced vitamin B12 levels. However, these preliminary findings require further confirmation.

ANAEMIA OF CHRONIC DISEASE: DIAGNOSTIC SIGNIFICANCE OF ERYTHROCYTE AND SEROLOGICAL PARAMETERS IN IRON DEFICIENT RHUEMATIOD ARTHRITIS PATEINTS

Erythrocyte and serological parameters were assessed in 44 anaemic rheumatoid arthritis (RA) patients to detect iron deficiency as assessed by stainable bone marrow iron. The anaemia was normochromic normocytic in 60% and hypochromic normocytic in 30% of those with anaemia of chronic disease (ACD). Iron deficiency was present in 55% and the anaemia was hypochromic microcytic in 54% and hypochromic normocytic or normochromic normocytic in 21%. Iron absorption was found to be higher in iron deficient patients. In ACD patients, iron absorption correlated inversely with ESR and CRP. For the detection of iron deficiency among RA patients with ACD, the MCV showed the highest specificity (90%) and predictive value (87%). Serum ferritin was the most sensitive (82%) and valid (86%) test. Combination of MCV, ferritin and transferrin resulted in 100% validity. It was concluded that iron deficiency can be detected accurately without bone marrow aspiration using combinations of blood parameters.

The anemia of chronic disease: Spectrum of associated diseases in a series of unselected hospitalized patients

Previous studies of the anemia of chronic disease (ACD) have generally begun with patients afflicted with one of the classical underlying diseases such as rheumatoid arthritis. The clinical spectrum of ACD has not been thoroughly examined. We hypothesized that many patients have an anemia with the characteristics of ACD but do not have one of the infectious, inflammatory, or neoplastic disorders usually associated with ACD. We therefore evaluated a series of consecutive, unselected, anemic patients admitted to a county hospital. All patients admitted to the medicine ward service of a county hospital were screened for anemia (hematocrit less than 40% in men, less than 37% in women). Additional laboratory data were collected on all anemic patients, except those with active gastrointestinal bleeding, hemolytic disease, or leukemia or multiple myeloma. The patients were divided into three groups on the basis of serum values indicating iron distribution: iron deficiency (serum ferritin less than 10 ng/mL), ACD (serum iron less than 60 micrograms/dL and serum ferritin more than 50 ng/mL), and all others (non-ACD). The hospital records of the patients in the latter two groups were reviewed and their diagnoses recorded. Seven patients with iron deficiency were not considered further. Ninety patients with ACD were compared with 75 patients with non-ACD. The anemia in ACD patients was more severe than most authors describe. The mean hematocrit was 31%, and 20% of patients had hematocrits below 25%. The anemia was usually normocytic (mean red cell volume [MCV] 86 fL), but 21% had an MCV less than 80 fL. The level of saturation of serum iron-binding capacity was quite low in ACD (mean 15%) and was normal in non-ACD (mean 31%). Renal insufficiency was common in both groups; serum creatinine values were more than 2 mg/dL in 31% of patients with ACD and 20% of non-ACD patients. Sixty percent of patients with ACD had a principal diagnosis that fell into the infectious, inflammatory, and neoplastic categories commonly associated with ACD. Renal insufficiency was the major diagnosis in 16%, and the principal diagnosis in 24% was a disease not commonly considered to be associated with ACD. In non-ACD patients, the principal diagnosis was an infectious, inflammatory, or neoplastic disease in 55%, renal insufficiency in 9%, and another disease in 36%. When ACD was defined by the abnormalities of iron distribution, which are its most consistent and widely accepted characteristics, the spectrum of associated diseases was much broader than the traditional categories of infectious, inflammatory, and neoplastic disorders, and the overlap with non-ACD was large. Until the etiologic and pathogenetic mechanisms of ACD are better understood, a flexible and inclusive view of this disorder seems appropriate.