Detection of iron restriction in anaemic and non-anaemic patients: New diagnostic approaches.

OBJECTIVE: The aim of this study was to detect iron restriction in non-anaemic patients and iron-restricted erythropoiesis (IRE) in patients with anaemia. METHOD: Haematologic indices and biochemical markers of iron deficiency (ID) were determined using the clinically accepted cut-off level for serum ferritin of ≤30 µg/L as reference of ID. To evaluate the prevalence of iron restriction and IRE in patients with higher ferritin levels, we used the thresholds of the markers of ID as reference. RESULTS: In the anaemic group, 17.1% of patients with ferritin levels >30 µg/L had IRE. The number of patients with IRE declined with increasing ferritin concentration. Approximately 14% of patients without anaemia and ferritin levels >30 µg/L had iron restriction because of iron-sequestration syndromes. About 30% of the anaemic patients with IRE had ferritin concentrations in the range >300 µg/L, but no patient of the non-anaemic group. CONCLUSIONS: Detection of iron restriction and IRE in patients with ferritin levels >30 µg/L is not possible with a single test used in isolation. Based on the results, we have developed a scoring system to provide optimal guidance for the evaluation of iron restriction in non-anaemic patients and iron-restricted erythropoiesis (IRE) in patients with anaemia.

Resistance exercise snacks improve muscle mass in female university employees: a prospective, controlled, intervention pilot-study.

Background: Although resistance training (RT) is essential to preserve musculoskeletal fitness and maintain a healthy, independent life into old age, few women perform RT. We investigated whether resistance exercise snacking (RES) could be an efficient training approach for the workplace health promotion (WHP) to minimize barriers for participation and facilitate RT in women in order to improve musculoskeletal fitness. Methods: This pilot-study followed a prospective, controlled intervention design. Female employees with sedentary occupations doing RT on less than 2 days/week before study participation were included. Participants self-selected for either intervention (IG) or control group (CG). While the IG [N = 15, mean age 42.1 (SD = 11.1) years] did 10 min of RES on working days for 12 weeks, the CG [N = 15, mean age 49.9 (SD = 9.7) years] was instructed to maintain their habitual physical activity. Primary endpoint was change in muscle mass. Secondary endpoint was change in maximum isometric strength. Balance, cardiovascular fitness, perceived health, and general life satisfaction was assessed for exploratory purpose. Measurements were taken before and after the intervention. Results: 12 participants of IG and 14 of CG completed the study. Muscle mass improved significantly more in the IG [+0.42 (SD = 0.54) kg] compared to the CG [-0.16 (SD = 0.51) kg] (p = 0.01, ƞ2p = 0.24). Strength did not change significantly between groups. Nevertheless, there was a trend for greater improvements in the IG compared to the CG for trunk extension, trunk flexion, and upper body push but not upper body pull. Regarding exploratory endpoints, no significant between-group changes were found. Despite their poor fitness, both groups perceived their health as good and had high life satisfaction before and after the intervention. Conclusion: RES could be an effective approach for the WHP to promote RT in inactive women with sedentary occupations and improve their muscle mass.

Serum hepcidin-25 in comparison to biochemical markers and hematological indices for the differentiation of iron-restricted erythropoiesis.

BACKGROUND: Biochemical markers have problems in distinguishing iron deficiency anemia (IDA) from anemia of chronic disease (ACD), and the combined state of iron-restricted erythropoiesis (IRE) with ACD (ACD/IRE). We investigated the extent to which hepcidin-25, a potential marker for the evaluation of iron metabolism, enables the differentiation of the states above, and to assess its correlation with convential markers of iron deficiency. METHODS: One hundred and fifty-five patients with anemia were classified as having IDA, ACD or ACD/IRE using clinical findings, biochemical markers and hematological indices. The diagnostic performance of hepcidin-25 alone or in combination with the reticulocyte hemoglobin content (CHr) was evaluated using receiver-operating characteristic curve analysis and multivariate analysis. Hepcidin-25 was determined using an isotope-dilution micro-HPLC-tandem mass spectrometry method. RESULTS: Hepcidin-25 correlated with biochemical markers of iron deficiency but not with hematological indices. Use of a hepcidin-25 cut-off of ≤ 4 nmol/L allowed the differentiation of IDA from ACD and ACD/IRE, but not the discrimination of ACD from ACD/IRE in patients with severe inflammation. Furthermore, the discrimination of ACD/IRE from ACD required the combination with CHr. CONCLUSIONS: Hepcidin-25 is primarily an indicator for decreased body iron levels, but not for IRE. The combination of hepcidin-25 with CHr in a diagnostic plot (hepcidin-25 plot) might be useful for the differentiation of ACD from ACD/IRE and IDA.

A new concept for the differential diagnosis and therapy of anaemia in cancer patients.

PURPOSE: This study aimed to prove the usefulness of the diagnostic plot, using the haemoglobin content of reticulocytes as a measure of functional iron deficiency (FID) and the ferritin index as a measure of iron availability, to customise anaemia treatment in cancer patients. METHODS: Based on results of this plot, cancer patients fulfilling practice guideline criteria to receive erythropoiesis-stimulating agents (ESAs) were allocated to treatment with ESAs alone, iron alone or the combination of both. Primary endpoint was the percentage of patients identified to require iron in addition or as an alternative to ESA therapy. RESULTS: Out of 303 patients screened, 286 were allocated to treatment: 204 patients were normochromic and iron replete and treated with ESAs alone, 22 had both FID and anaemia of chronic disease and were treated with ESAs and parenteral iron, and 60 were iron-depleted and treated with iron only. After 8 weeks, a haemoglobin increase >1 g/dL from baseline was shown by 56% of patients treated with ESAs alone, by 100% of patients receiving the combination, by 50% of normochromic and by 73% of hypochromic iron-depleted patients receiving iron only. Acute phase reaction did not diminish the response rate to ESAs. CONCLUSIONS: The diagnostic plot was superior to transferrin saturation and ferritin in predicting iron availability in hypochromic patients treated with ESAs and proved useful to select treatment for anaemia in cancer patients.

Predictive Factors for Vitamin D Concentrations in Swiss Athletes: A Cross-sectional Study.

Vitamin D concentrations corresponding to 75 nmol/L 25(OH)D have been associated with maintained muscle function, growth and regeneration, optimal bone health and immunology in athletes. The objective of this study was to investigate the prevalence and predictors of insufficient 25(OH)D concentrations in athletes. Six hundred three Swiss athletes were assessed. 25(OH)D was analysed by high-performance liquid chromatography (HPLC). A standardized questionnaire was used to gather information about potential predictors for 25(OH)D concentrations; 50.5% showed insufficient 25(OH)D concentrations. Differences in predicted probability of insufficient 25(OH)D were found for those vitamin D supplemented (42%) versus not supplemented (52%), in those performing indoor (58%) versus outdoor sports (43%), and during the sun-deprived seasons of fall (49%), winter (70%) and spring (57%) compared with summer (17%). Higher BMI z-scores and age were associated with higher 25(OH)D concentrations. In conclusion, insufficient 25(OH)D concentrations were common among athletes especially at a younger age, among those not supplemented, in athletes who trained indoors, and during the sun-deprived seasons. Because the prevalence of insufficient 25(OH)D concentrations in this study was high, regular supplementation in athletes may be indicated, except perhaps during the summer season. Further research is needed to determine which 25(OH)D concentrations lead to optimal health and performance in athletes.

The diagnostic plot: a concept for identifying different states of iron deficiency and monitoring the response to epoetin therapy.

Iron balance is regulated by the rate of erythropoiesis and the size of the iron stores. Anemia that accompanies infection, inflammation, and cancer (anemia of chronic disease) features normal or increased iron stores, although patients may have functional iron deficiency, namely, an imbalance between iron requirements of the erythroid marrow and the actual supply. The proportion of hypochromic red cells and the hemoglobin content of reticulocytes are direct indicators of functional iron deficiency. Biochemical markers, especially the soluble transferrin receptor/log ferritin ratio (ferritin index), are useful indicators of the iron supply to erythropoiesis. The relationship between functional iron deficiency (reticulocyte hemoglobin content) and iron supply to erythropoiesis (ferritin index) can be described in a diagnostic plot. In normoproliferative and hypoproliferative erythropoiesis, the plot allows the differentiation of classic iron deficiency from anemia of chronic disease and the combined state of functional iron deficiency with anemia of chronic disease. The therapeutic implications of the plot are to differentiate patients into those who should be administered iron supplements, epoetin, or a combination of epoetin and iron. In patients receiving epoetin therapy, the plot is an important tool for monitoring erythropoietic activity, functional iron deficiency, and adequate iron stores for new red cell production. Enhanced erythropoiesis is reflected quantitatively by the ferritin index vector. A transgression of the 1.5 (3.2) cut-off value for the ferritin index indicates that extra doses of iron need to be administered to increase the body's iron stores. A lack of increase or a reticulocyte hemoglobin content below 28 picograms indicates functional iron deficiency. The diagnostic plot is a model for differentiating iron-deficient states and predicting those patients who will respond to epoetin therapy.

Renal failure--measuring the glomerular filtration rate.

BACKGROUND: Chronic renal disease is common, and its prevalence is rising. Its main causes are hypertension and diabetes mellitus. An abnormally low glomerular filtration rate (GFR) often escapes medical notice in the earliest, most treatable stage, so that an increasing number of patients progress to end-stage renal failure. Early recognition of low GFR would thus be an important clinical advance. METHODS: The authors selectively review the literature retrieved by a PubMed search on the topic and also present their own clinical and laboratory data. RESULTS: Chronic renal failure can be detected early by direct measurement of the GFR with the aid of an exogenous filtration marker. Such techniques are costly and time-consuming and are therefore indicated only for patients at special risk. Chronic renal disease can also be diagnosed early with the aid of the endogenous filtration markers creatinine and cystatin C, which serve as indicators of a low GFR. The serum levels of these two substances are not taken as measures of GFR in themselves, but are rather entered into predictive equations for the estimation of GFR. Cystatin C-based equations seem to be more sensitive indicators of low GFR than creatinine-based equations. CONCLUSIONS: Creatinine- and cystatin C-based equations for the estimation of GFR are valuable tools for the early diagnosis of chronic renal disease and for disease staging according to the US National Kidney Foundation criteria.

Renal function--estimation of glomerular filtration rate.

Assessment and follow-up of renal dysfunction is important in the early detection and management of chronic kidney disease. The glomerular filtration rate (GFR) is the most accurate measurement of kidney disease and is reduced before the onset of clinical symptoms. Drawbacks to the measurement of GFR include the high cost and incompatibility with routine laboratory monitoring. Serum creatinine determination is a mainstay in the routine laboratory profile of renal function. The measurement of serum cystatin C has been proposed as a more sensitive marker for GFR. According to National Kidney Foundation-K/DOQ1 clinical guidelines for chronic kidney disease, serum markers should not be used alone to assess GFR. Based on prediction equations, clinical laboratories should report an estimate of GFR, in addition to reporting the serum value. In this article, information is presented on how best to estimate GFR using prediction equations for adults and for children. Using serum creatinine concentration with the Modification of Diet in Renal Disease (MDRD) study equation offers a suitable estimation of GFR in adults. The cystatin C prediction equation with the use of a prepubertal factor seems superior to creatinine-based prediction equations in children of <14 years.

Anemia of chronic disease: pathophysiology and laboratory diagnosis.

Classic iron deficiency (ID) does not represent a challenge for the laboratory and physicians. The anemia that accompanies infection, inflammation, and cancer, commonly termed anemia of chronic disease (ACD), features apparently normal or increased iron stores. However, 20% of these patients have iron-restricted erythropoiesis (functional ID), an imbalance between the iron requirements of the erythroid marrow and the actual iron supply. Functional ID leads to a reduction in red cell hemoglobiniza-tion, causing hypochromic microcytic anemia. The diagnosis of functional ID in real time is based on measuring the hemoglobin content of reticulocytes. An examination of the biochemical markers of iron metabolism demonstrates weaknesses in the diagnosis of functional ID. We developed a diagnostic plot for the assessment of iron status in ACD and the detection of advancing ID in patients with ID, ACD, and the combined state of functional ID and ACD. The plot indicates the correlation between a marker of the iron supply for erythropoiesis (ie, the ratio of the soluble transferrin receptor value to the logarithm of the ferritin value) and the reticulocyte hemoglobin content and functions as a marker of iron demand. The diagnostic plot shows good selectivity for assessing the iron status of disease-specific anemias such as classic ID, end-stage renal failure, cancer-related anemia, and the anemia of infection and inflammation. The therapeutic implications of the diagnostic plot are to differentiate patients who should be administered oral iron supplements, recombinant human erythropoietin (r-HuEPO), or a combination of r-HuEPO and iron. The response of erythropoiesis to r-HuEPO depends on the iron supply and the proliferation of erythropoiesis. The lack of an increase or a decrease in reticulocyte hemoglobin levels indicates a nonresponder to r-HuEPO or functional ID.

Reticulocyte hemoglobin measurement--comparison of two methods in the diagnosis of iron-restricted erythropoiesis.

The aims of this study were to diagnose iron-restricted erythropoiesis (functional iron deficiency) in patients with classic iron deficiency (ID), anemia of chronic disease (ACD) and the combined state of ID/ACD with the use of two hematological methods for the measurement of reticulocyte hemoglobinization. In comparison, the biochemical markers of iron status were determined. We studied 474 anemic patients admitted to hospital with a broad spectrum of diseases. We measured indicators of reticulocyte hemoglobinization. CHr was determined on an Advia 120 hematology analyzer. A Sysmex XE-2100 hematology analyzer was used to determine RET-Y, the forward scatter of fluorescence-labeled reticulocytes, which can also be expressed as the reticulocyte hemoglobin equivalent (RET-H(e)), as well as RBC-Y, the forward scatter of fluorescence-labeled erythrocytes, which can be expressed as the erythrocyte hemoglobin equivalent. Ferritin, soluble transferrin receptor (sTfR) and the sTfR/log ferritin ratio (sTfR-F index) were used as biochemical markers. The comparison of RET-Y with CHr demonstrated an excellent curvilinear relationship between the two parameters. The normal reference range for Ret-Y was 1630-1860 arbitrary units (AU); mathematical transformation to RET-H(e) gave a range of 28.2-35.7 pg. Correlations of biochemical iron markers with RET-H(e) were as weak as with CHr in patients with ACD and acute phase response. In a diagnostic plot to identify iron status, RET-H(e) could replace CHr without any loss of sensitivity or specificity. Patient mismatch analysis between RET-H(e) and CHr in the diagnostic plot demonstrated agreement for 449 of 474 patients (94.4%). Patient specific anemia mismatches were 2.9-6.2%. According to our results, the indicators of reticulocyte hemoglobinization, RET-H(e) and CHr, measure the same phenomenon. RET-H(e) is as valuable as CHr for the diagnosis of iron-restricted erythropoiesis. The combination of RET-H(e) and the sTfR-F index in a diagnostic plot offers an attractive tool for the evaluation of iron status and identification of the progression of ID.

Biochemical markers and hematologic indices in the diagnosis of functional iron deficiency.

BACKGROUND: The hypochromic red cell is a direct indicator of functional iron deficiency (ID) in contrast to the majority of biochemical markers, which measure functional ID indirectly via iron-deficient erythropoiesis. The aim of this study was to evaluate the extent to which these biochemical markers can distinguish ID from anemia of chronic disease (ACD) as well as from the combined state of functional ID/ACD, using red cell hemoglobinization as the gold standard. METHODS: We studied 442 patients with various disease-specific anemias and 154 nonanemic patients. As indicators of red cell hemoglobinization, we measured the reticulocyte hemoglobin content (CHr) and the proportion of hypochromic red cells (HYPO), using an Advia 120 hematology analyzer. Ferritin, transferrin, transferrin saturation, and the concentration of the soluble transferrin receptor (sTfR) were determined by ELISA and immunoturbidimetric assay. The sTfR/log ferritin ratio (sTfR-F index) was used as an additional marker for biochemical identification of iron-deficient erythropoiesis. RESULTS: In a control group (n = 71), the 2.5 percentile values were 28 pg for CHr and 5% for HYPO. These values were used to indicate unimpaired red cell hemoglobinization and absence of functional ID. In patients with deficient red cell hemoglobinization but no acute-phase response (APR), iron-deficient erythropoiesis was indicated by serum ferritin and sTfR-F index values < or =20.8 microg/L and >1.5, respectively. Corresponding values in patients with APR were < or =61.7 microg/L and >0.8, respectively. The positive likelihood ratios for the biochemical markers and the sTfR-F index for identifying iron-restricted erythropoiesis in patients with and without APR were 2.6-6.9 and 4.3-16.5, respectively. CONCLUSION: In APR patients, biochemical markers demonstrate weaknesses in the diagnosis of functional ID as defined by hematologic indices. Use of diagnostic plots to illustrate the relationship between the sTfR-F index and CHr allows the progression of ID to be identified, regardless of whether an APR is present.

Multicenter evaluation of a fully mechanized soluble transferrin receptor assay on the Hitachi and cobas integra analyzers. the determination of reference ranges.

Soluble transferrin receptor (sTfR) is reported to be a reliable marker for the diagnosis of iron deficiency, especially when iron metabolism is influenced by inflammatory disorders such as infection, chronic inflammation and cancer-related anemia. In the present multicenter study the analytical performance of a recently introduced, latex-enhanced immunoturbidimetric assay for the determination of soluble transferrin receptor (Tina quant [a] sTfR, Roche Diagnostics) on different fully mechanized analyzers such as Hitachi 917 and 911, and Cobas Integra 400 and 700 was evaluated. Within-run and between-run imprecision showed good results (CV<5% and <7%, respectively). The assay was found to be linear over a wide measuring range (0.4-35 mg/l). Endogenous substances did not interfere with the test results. Comparison of serum sTfR concentrations with those of heparinized plasma revealed good correlation (r>0.976). Method comparison with an existing fully mechanized method as well as with ELISA tests for sTfR showed very good correlation (r>0.987). Because of the lack of international standardization the results differed from each other up to 2.5-fold. The 95% of serum levels in healthy individuals ranged from 1.9 to 4.4 mg/l (n=427). However, the reference ranges should be reported in a sex-dependent manner, as 2.2-5.0 mg/l for men (n=211) and as 1.9-4.4 mg/l for premenopausal (n=216) and postmenopausal (n=45) women. The Tina quant [a] sTfR assay enables the precise, accurate, rapid and convenient determination of sTfR concentrations for routine clinical chemistry purposes.