Serum soluble transferrin receptor and the prediction of marrow aspirate iron results in a heterogeneous group of patients.

Serum soluble transferrin receptor (sTfR) concentration has been evaluated in the diagnosis of iron deficiency in otherwise healthy individuals and in patients with rheumatoid arthritis, but has not been studied in a general population of patients with complicated clinical presentations. In this study, 145 anaemic patients with a variety of medical conditions undergoing diagnostic bone marrow aspiration for any reason were tested by a complete blood count, a panel of biochemical tests to evaluate iron status, bone-marrow aspirate iron stain, and serum sTfR concentration. Sixteen per cent lacked stainable iron in the marrow aspirate. All biochemical parameters differed significantly between patients with or without stainable marrow iron. The sTfR assay was significantly more sensitive but less specific than other iron status assays in identifying the absence of stainable iron. Logistic regression analysis demonstrated that only sTfR and ferritin contributed independently to the prediction of marrow iron status. Serum ferritin alone was highly specific but insensitive. A decision algorithm combining serum ferritin and sTfR was as sensitive as TfR and as specific as serum ferritin. The measurement of serum sTfR, especially in conjunction with serum ferritin, is a valuable addition to the existing methods for predicting the results of marrow aspirate iron stains.     

Serum transferrin receptor levels in patients undergoing evaluation of iron stores: correlation with other parameters and observed versus predicted results

Serum transferrin receptor (sTfR) concentrations were measured in specimens from 77 patients undergoing serum ferritin determination, and the results correlated with serum ferritin, serum iron, serum total iron-binding capacity (TIBC) saturation, erythrocyte mean corpuscular volume (MCV), and mean corpuscular haemoglobin (MCH). All parameters exhibited the expected inverse correlation with sTfR; this correlation was statistically significant for all parameters except serum iron concentration. The frequency with which iron deficiency (defined as absence of stainable marrow iron) is observed in patients with particular ferritin values in this centre was determined and used to estimate the expected number of iron deficient patients in the present study. In no setting were significantly fewer sTfR levels > 3.05 μg/ml observed than expected. However, significantly greater than expected numbers of elevated sTfR values were observed in patients with serum ferritin > 220 μg/l (P = 0.002). The results suggest that the sTfR level is probably not useful as a single test for identification of iron deficiency in unselected patients.     

Factor V Leiden mutation carriership and venous thromboembolism in polycythemia vera and essential thrombocythemia

The aim of the present study is to evaluate in an elderly hospitalized population the diagnostic value of the serum transferrin receptor (sTfR) in distinguishing IDA (iron deficiency anemia) from ACD (anemia of chronic disease) as compared to conventional laboratory tests of iron metabolism, especially serum ferritin. In a prospective study, 34 patients with IDA and 38 patients with ACD (a chronic disorder in 23 and an acute infection in 15) were evaluated using iron status tests including serum transferrin receptor assay. The iron stores were assessed by bone marrow examination. sTfR levels were elevated (>28.1 nmol/L) in 68% of the IDA patients but also in 43% of the patients with ACD-chronic inflammation and 33% with ACD-acute infection. Serum ferritin was the best test to differentiate IDA from ACD patients. We conclude that serum ferritin is a more sensitive and specific parameter than the sTfR assay to predict the bone marrow iron status in an elderly anemic population.     

Iron metabolism, sickle cell disease, and response to cyanate.

In an attempt to understand the variability of the hematologic response to oral sodium cyanate, iron metabolism was studied in a group of 39 patients with sickel cell disease. Eleven of the 39 patients were found to have no stainable iron in the marrow despite the fact that patients with sickle cell disease are generally considered to have hemosiderosis. The mean per cent saturation and total iron-binding capacity were in the low-normal range in sickle cell patients whether or not stainable iron was present in the bone marrow aspirate. Serum ferritin concentrations, on the other hand, were found to be high in both groups (greater than 500 mu g/liter) when compared to controls (60 mu g/liter). The high serum ferritin levels denoted significant total-body iron deposition which may be unavailable for normal metabolic processes. One patient with no stainable iron in the bone marrow aspirate did respond to iron therapy alone with an increase in hemoglobin concentration. Serum ceruloplasmin levels were also found to be high in sickle cell disease patients. The ability to respond to oral cyanate therapy was correlated with the amount of stainable iron in the bone marrow aspirate. These studies emphasize the necessity of a reevaluation of iron metabolism in the pathophysiology and treatment of sickle cell disease.     

Serum ferritin levels in anemia of rheumatoid arthritis

Thirty-five anemic patients with rheumatoid arthritis were studied to determine the relationship between serum ferritin levels and body iron status, as assessed by the grading of bone marrow iron stores. The incidence of greatly reduced or absent marrow iron stores was 60%. Peripheral blood smear, RBC indices, serum iron, and iron binding capacity correlated poorly with stainable marrow iron. Serum ferritin levels only correlated approximately with iron stores, and in iron deficient rheumatoid patients the levels were higher than would be expected in patients with uncomplicated iron deficiency. The study shows that reduced marrow iron stores is common in patients with rheumatoid arthritis, and that the serum ferritin concentration may provide a useful indication of reduced body iron stores in these subjects, but only if a range of normal values can be established for this disease.     

Diagnosis of iron deficiency: evaluation of the "soluble transferrin receptor/transferrin" ratio

OBJECTIVE: This study was aimed at determining the diagnostic value of conventional laboratory tests regarding the iron status and serum transferrin receptor in hospitalized patients. METHODS: Patients who had to undergo bone marrow aspirate examination were included in this 8-month prospective study. Iron deficiency was defined as the absence of stainable iron on bone marrow examination. Patients with stainable iron were included in the control group. The higher value of diagnostic efficacy determined the cut-off value for each parameter of the iron status. RESULTS: Twenty-one patients (17 females, four males) (mean age: 52 years) with iron deficiency and 33 control subjects (20 females, 13 males) (mean age: 60 years) were included in the study. The ratio serum transferrin receptor/serum ferritin had the best diagnostic efficiency (78%) with a sensitivity of 81% and a specificity of 97%. Serum ferritin alone with a cut-off value of 60 micrograms/L had the same specificity (97%) but a lower sensitivity (76%). The diagnostic value of all other analyzed tests was below 66% (transferrin alone, mean corpuscular volume, transferrin saturation, iron, serum transferrin receptor alone, red cell distribution width). CONCLUSION: Among in-patients, ferritin remains the first intention test to diagnose iron deficiency, but the cut-off value should be increased (60 micrograms/L in this study). The ratio "serum transferrin receptor to serum ferritin" provides the highest specificity with a higher cost and should be used only in doubtful cases.     

The usefulness of serum transferrin receptor and ferritin for assessing anemia in rheumatoid arthritis: comparison with bone marrow iron study

OBJECTIVES: This study was aimed at investigating the usefulness of serum transferrin receptor (sTfR) and ferritin in anemic patients with rheumatoid arthritis (RA) compared with bone marrow storage iron and other tests for anemia. METHODS: Fifty-five anemic RA patients underwent anemia study. Bone marrow iron stain was performed in 18 patients. sTfR and serum ferritin levels were compared with bone marrow iron stores. RESULTS: (1) Mean sTfR concentration was 2.63+/-1.91 mg/L, (2) sTfR correlated with most indicators of anemia, (3) sTfR showed no correlation with CRP and ESR, whereas ferritin did, and (4) sTfR was higher in the "iron depleted" subgroup than in the "iron nondepleted" subgroup in bone marrow study. CONCLUSION: The measurement of sTfR and ferritin is useful in finding the cause of anemia in RA and is a possible substitute for invasive bone marrow iron study.     

Single value of serum transferrin receptor is not diagnostic for the absence of iron stores in anaemic patients with rheumatoid arthritis

Serum transferrin receptor (sTfR) concentrations were measured in anaemic patients with rheumatoid arthritis (RA). Serum transferrin receptor concentrations were positively correlated with the percentage of hypochromic cells and negatively correlated with MCH. There was a weak correlation with serum ferritin (sFn) concentration but not with reticulocyte count. Thus, high concentrations of sTfR indicate iron-deficient erythropoiesis rather than levels of storage iron in the tissues. Patients were divided into three groups on the basis of sFn concentration: those with probable tissue iron deficiency, those with adequate iron stores and those with intermediate values of sFn which did not allow classification. The median sTfR concentration was significantly higher in the iron-deficient group than in the other two groups but because of overlap between the three groups, a single sTfR value was of limited value in determining the level of storage iron in an individual with RA.     

Serum transferrin receptor

Transferrin receptors (TfRs) are the conventional pathway by which cells acquire iron for physiological requirements. Under iron-deficient conditions there is an increased concentration of surface TfR, especially on bone marrow erythroid precursors, as a mechanism to sequester needed iron. TfRs are also present in the circulation, and the circulating serum TfR (sTfR) level reflects total body TfR concentration. Under normal conditions erythroid precursors are the main source of sTfR. Disorders of the bone marrow with reduced erythroid precursors are associated with low sTfR levels. The sTfR concentration begins to rise early in iron deficiency with the onset of iron-deficient erythropoiesis, and continues to rise as iron-deficient erythropoiesis progressively worsens, prior to the development of anemia. The sTfR level does not increase in anemia of chronic inflammation, but is increased when anemia of chronic inflammation is combined with iron deficiency. The sTfR level is also increased in patients with expanded erythropoiesis, including hemolytic anemias, myelodysplastic syndromes, and use of erythropoietic stimulating agents. The ratio of sTfR/ferritin can be used to quantify the entire spectrum of iron status from positive iron stores through negative iron balance, and is particularly useful in evaluating iron status in population studies. The sTfR/log ferritin ratio is valuable for distinguishing anemia of chronic inflammation from iron deficiency anemia, whether the latter occurs alone or in combination with anemia of chronic inflammation.     

The usefulness of serum transferrin receptor for discriminating iron deficiency without anemia in children

We determined serum transferrin receptor (sTfR), serum erythropoietin and hematologic and biochemical iron parameters in 251 healthy children. The levels of sTfR were significantly higher in children with storage iron deficiency but had a poor sensivity for recognizing iron deficiency without anemia. When ferritin values cannot accurately demonstrate the iron deficiency in children, the sTfR/ferritin ratio or sTfR-log ferritin is recommended to discriminate iron deficiency in the absence of anemia.     

Soluble transferrin receptors and ferritin in Type 2 diabetic patients.

AIM: To determine circulating transferrin receptor levels (sTfR) in Type 2 diabetic patients to evaluate whether serum ferritin reflects iron body stores or inflammation in diabetic population. METHODS: A total of 84 consecutive Type 2 diabetic patients and 60 healthy subjects matched by age and gender were included in this case-control study. Ferritin concentration was measured by a turbidimetric method and sTfR concentration were determined by nephelometry. RESULTS: Diabetic patients have higher serum ferritin levels than control subjects [114 ng/ml (12-831) vs. 74 ng/ml (11-697); P = 0.006]. However, no differences in sTfR concentrations were observed between both groups [1.27 mg/l (0.69-2.47) vs. 1.24 mg/l (0.77-2.80); P = NS]. A negative correlation between ferritin and sTfR concentration was detected in control subjects but not in diabetic patients. CONCLUSIONS: Serum ferritin levels are increased in Type 2 diabetic patients in the absence of a reciprocal decrease of sTfR. This finding suggests that elevated ferritin levels in Type 2 diabetes are mainly as a result of inflammatory mechanisms rather than iron overload.     

血清转铁蛋白受体对贫血患者鉴别诊断的临床意义

目的比较各项铁指标在慢性病贫血(ACD),缺铁性贫血(IDA)及ACD合并IDA中的变化规律,明确血清转铁蛋白受体(sTfR)的临床意义.方法设健康志愿者28例为对照组,同时设IDA组29例,ACD组 56例,分别进行血清铁(SI)、总铁结合力(TIBC)、运铁蛋白饱和度(TS)、血清铁蛋白(SF)及sTfR检测,并对26例慢性病患者做骨髓铁染色,根据sTfR值将ACD组分为(1)sTfR值正常组(ACD1组)27例(sTfR≤20.0 nmol/L ),(2)sTfR值升高组(ACD2组)29例(sTfR>20.0 nmol/L).结果 IDA组与其他各组相比,其中平均红细胞体积(68.0±11.3)fl为最小;SI、TS及SF值分别是(19.6±10.1) mg/L、(5.5±2.3)%和(4.3±2.8)μg/L,与对照组(81.7±30.6) mg/L、(27.0±12.0)%和(43.3±26.8) μg/L相比水平明显下降(P≤0.01);sTfR水平(67.2±40.3) nmol/L明显高于对照组(15.6±4.1) nmol/L,P≤0.01.ACD1组SF值(627.3±40.3) μg/L,明显高于其他各组(P≤0.01); SI(60.7±28.7) mg/L和TS(21.1±9.8)%与对照组差异无显著性(P>0.05),10例骨髓铁染色均无缺铁.ACD2组SF值(320.5±156.0) μg/L,高于对照组而低于ACD1组(P≤0.01),16例骨髓铁染色中14例显示铁缺乏,占88%.结论 sTfR值的升高有效地反映了体内铁缺乏状况,是诊断IDA更为敏感的指标,并且较少受慢性炎症性疾病的影响,可与ACD有效鉴别.     

A bone marrow report of absent stainable iron is not diagnostic of iron deficiency

The absence of stainable iron in a bone marrow aspirate is widely considered to be diagnostic of iron deficiency anemia (IDA). We re-evaluated this concept by studying a cohort of 108 consecutive bone marrow specimens from an unselected series of patients who were seen at a hematology clinic and in whom iron stores were reported as being absent. A review of the pathologic reports revealed 19 inadequate specimens and 15 with decreased, but not absent, iron stores. Thus, only 74 of the 108 cases had been accurately reported. In 37 of these cases, adequate clinical and laboratory data were available and allowed further analysis. In 18 patients, careful review of patient history, physical examination, results of endoscopic procedures, and follow-up information failed to suggest the presence of IDA (group A). The review process in the remaining 19 patients suggested the possibility of IDA (group B). Significant differences between groups A and B were observed in serum ferritin (P = 0.001) and red blood cell mean corpuscular volume (P = 0.004). In contrast, the two groups did not differ significantly in hemoglobin concentration, serum iron, total iron-binding capacity, transferrin saturation, or erythrocyte sedimentation rate. These observations suggest that a pathology report of absent bone marrow hemosiderin may be inaccurate in more than 30% of cases and, even when accurate, may not necessarily signify the presence of IDA. Measurement of the serum ferritin level is needed to confirm a clinical diagnosis.     

Single values of serum transferrin receptor and transferrin receptor ferritin index can be used to detect true and functional iron deficiency in rheumatoid arthritis patients with anemia

OBJECTIVE: To elucidate the use of serum transferrin receptor (sTfR) to distinguish between iron-deficiency anemia (IDA) and anemia of chronic disease (ACD), and to establish an improved scheme to identify functional iron deficiency (FID) in rheumatoid arthritis (RA) patients with anemia. METHODS: We studied 30 anemic RA patients whose iron status was confirmed by bone marrow examination and determination of the sTfR level, serum ferritin level, and sTfR-log ferritin index (TfR-F Index). All patients with diminished or exhausted iron stores (n = 18) received oral iron supplementation. RESULTS: Baseline values of sTfR and the TfR-F Index predicted the response correctly in all patients who received supplementation treatment and were normal in 10 of 11 patients with normal initial iron stores (ACD). CONCLUSION: The results of this study elucidate the roles of sTfR and the TfR-F Index in the differential diagnosis between IDA and ACD and provide direct evidence that these parameters are useful in detecting FID, irrespective of the concurrent iron storage status.     

Red cell ferritin and iron stores in patients with chronic disease

Serum and red cell ferritin were determined in a heterogeneous group of 59 patients with chronic disease undergoing a bone marrow biopsy. There was very little correlation between serum and red cell ferritin (r = 0.53). Although serum ferritin increased in relation to increased bone marrow iron stores, only 1 out of 8 patients with absent marrow iron stores and none of 8 patients with reduced marrow iron stores had a decreased serum ferritin. In contrast, 6 of 8 patients with absent iron stores had a reduced red cell ferritin concentration. There was no significant difference between the mean red cell ferritin of the patients with reduced, normal and mild-moderately increased marrow iron stores (30, 26 and 34 ag/cell). Red cell ferritin was decreased in 78% of a group of 32 patients with a low mean cell volume. In the patients studied, red cell ferritin was a better indicator of absent iron stores than serum ferritin. However, red cell ferritin did not detect a reduction in the iron status until the marrow iron stores were completely depleted. Apparently, during normal erythropoiesis the primitive erythroblasts continue to take up iron irrespective of the amount of iron available in the stores.     

Iron deficiency in inflammatory bowel disease

The prevalence of iron-deficiency anemia was defined in 105 patients with inflammatory bowel disease and an appraisal made of the diagnostic value of serum ferritin for the assessment of iron stores. Iron deficiency, defined by the absence of bone-marrow hemosiderin was found with anemia in 36% of 41 patients with ulcerative colitis (UC) and 22% of 64 patients with Crohn's disease (CD). Iron deficiency without impaired erythropoiesis was detected in an additional 32% of patients with UC and 2% with CD. Anemia with plentiful bone-marrow iron was present in 33 (51%) of patients with CD, only one of whom had vitamin B₁₂ deficiency. Red blood cell morphology, RBC indices, serum iron, and percent transferrin saturation correlated poorly with stainable marrow iron. Serum ferritin, assayed in samples from 45 patients, was <18 ng/ml in 4/12 with iron-deficiency anemia and 0/5 with absent marrow iron and a normal hemoglobin level; values >55 ng/ml were invariably associated with the presence of marrow hemosiderin. Based on a lower normal limit of 18 ng/ml, the serum ferritin had an excellent predictive value (100%) but a high predictive error (32%) in the diagnosis of iron deficiency in inflammatory bowel disease. Serum ferritin >55 ng/ml ruled out iron deficiency as the basis for anemia.     

Serum soluble transferrin receptor concentration is an accurate estimate of the mass of tissue receptors

OBJECTIVE: Serum levels of the soluble transferrin receptor (sTfR) vary depending on the erythropoietic activity and iron status. In vitro, sTfR shed in the incubation medium correlates well with cellular TfR, but this relationship has never been established in vivo. To determine the value of serum sTfR as a quantitative marker of the body mass of tissue TfR, we designed experiments to examine the correlation between serum sTfR and tissue TfR in rats with various degrees of erythropoietic activity or iron status. MATERIALS AND METHODS: We studied changes in erythropoietic activity in normal rats as well as in animals experiencing hemolysis, phlebotomy-induced iron deficiency, transfusion- or thiamphenicol-induced erythroid aplasia, or inflammation. At the end of follow-up, ferrokinetic studies were performed and animals were sacrificed. Organs were isolated and homogenized to determine the total mass of tissue TfR from the sum of tissue solubilized TfR in the bone marrow, spleen, liver, and blood cells (direct method). An indirect method was developed to derive the corporeal mass of tissue TfR from a representative marrow sample. RESULTS: As expected, serum sTfR and total mass of tissue TfR varied as a function of iron status and erythropoiesis. Relative erythroid expansion in the spleen was greater than in the bone marrow. With the exception of phlebotomized animals, the indirect method correlated very well with direct measurements of the total mass of tissue TfR (r = 0.97, p < 0.0001). There was a close relationship between the total mass of tissue TfR and the total mass of serum sTfR (r = 0.79, p < 0.0001). Serum sTfR represented approximately 5-6% of the total mass of tissue TfR in most experimental situations, but this ratio was twice as high during iron-restricted erythropoiesis. In addition, the ratio could be higher or lower in nonsteady-state situations, because changes in tissue TfR occurred faster than those of serum sTfR. CONCLUSIONS: Serum sTfR represents a constant proportion of the total mass of tissue TfR over a wide range of erythropoietic activity. However, iron deficiency results in a higher proportion of serum sTfR, and the pace of change in serum sTfR levels is slower than that of tissue TfR mass.     

Serum soluble transferrin receptor in the diagnosis of iron deficiency in chronic liver disease

Fifty-one consecutive patients with chronic liver disease (CLD) underwent investigations of their iron status (full blood count, serum iron [Fe], total iron binding capacity [TIBC], transferrin saturation [TS], serum ferritin and serum soluble transferrin receptor [sTfR] level). Twenty-six patients were anaemic; 12 patients had iron deficiency, and 10 had iron deficiency anaemia (IDA). The median (range) sTfR in the IDA patients was 16.6 (11.2–24.8) mg/l, compared with 6.6 mg/l (11.2–24.8) in the 16 patients with anaemia due to other causes (P = 0.01). The sensitivity of sTfR for diagnosing iron deficiency in CLD was 91.6% (100% if only anaemic patients are included) and the specificity was 84.6%. Patients with haemolysis and recent blood loss may have falsely elevated sTfR levels. The results suggest that the sTfR is as useful as serum ferritin in identifying a potentially treatable cause of anaemia in CLD.     

Value of serum ferritin as an index of iron deficiency in elderly anaemic patients

Serum ferritin was correlated with bone marrow iron stores in 35 elderly anaemic patients. All 19 patients with low serum ferritin had iron deficiency as assessed on bone marrow examination, whereas six patients with low or absent bone marrow iron stores had serum ferritin within normal range. A low serum ferritin invariably indicates iron deficiency and has a better correlation than low serum iron. Serum ferritin should be included in the initial investigation of the anaemic elderly.     

Diagnosis of iron deficiency anemia in the elderly by transferrin receptor-ferritin index

BACKGROUND: The diagnosis of iron deficiency anemia (IDA) in the elderly is difficult because of the prevalence of chronic diseases, which can cause anemia with high ferritin levels, even in the presence of iron deficiency. Therefore, we studied the sensitivity and specificity of a serum transferrin receptor assay, which is not affected by chronic diseases, in the diagnosis of IDA in elderly patients. METHODS: We performed a prospective controlled study of 49 consecutive male and female patients older than 80 years who were admitted to an acute geriatric department. Bone marrow aspirate confirmed IDA in all 49 patients. Fourteen additional patients, also older than 80 years, with anemia but without evidence of iron deficiency on results of bone marrow examination, served as a control group. All patients underwent evaluation by means of a detailed medical history and results of complete physical examination, routine blood tests, and specific tests for diagnosis and evaluation of anemia. Examination of bone marrow aspirate was performed for all patients. Levels of transferrin receptor in serum were determined by means of a specific enzyme-linked immunosorbent assay. The transferrin receptor-ferritin index (TR-F index) was defined as the ratio of serum transferrin receptor level to log ferritin level. RESULTS: Only 8 patients could be diagnosed as having IDA by means of routine blood test results (serum iron, ferritin, and transferrin saturation levels). In contrast, the TR-F index disclosed IDA in 43 of the 49 patients, thus increasing the sensitivity from 16% to 88%. CONCLUSIONS: The diagnosis of IDA in the elderly by means of routine blood tests has a very low sensitivity. The TR-F index is much more sensitive, and when results are positive, the TR-F index can eliminate the need for bone marrow examination.