Serum hepcidin‐25 may replace the ferritin index in the Thomas plot in assessing iron status in anemic patients

Introduction: Biochemical markers of iron deficiency do not distinguish iron‐deficient anemia (IDA) from the anemia of chronic disease (ACD) and the combined state of ACD/IDA. Serum hepcidin‐25 might be a marker resolving this problem. We investigated the extent to which serum hepcidin‐25 enables the differentiation of the states above in comparison with the ferritin index plot, the so‐called Thomas plot [soluble transferrin receptor (sTfR)/log ferritin and the reticulocyte hemoglobin content (CHr)]. Methods: Serum hepcidin‐25 was determined in 155 anemic patients who were classified as having latent iron deficiency (latent ID), IDA, ACD, or ACD/IDA using the ferritin index plot (Thomas plot). Hepcidin‐25 was determined using an isotope‐dilution micro‐HPLC‐tandem mass spectrometry method. The ability to discriminate among these states based on serum hepcidin‐25 alone or in combination with the CHr was evaluated in a receiver operating characteristic curve analysis and a comparison with the recently established ferritin index plot. Results: Serum hepcidin‐25 correlated with ferritin and the ferritin index. Use of a hepcidin‐25 cutoff level of ≤4 nmol/l allowed the differentiation of IDA from ACD and ACD/IDA. Furthermore, the discrimination of ACD/IDA from ACD required combination with CHr in a new plot (hepcidin‐25 and the CHr). The hepcidin‐25 plot and the ferritin index plot showed a good correspondence in the differentiation of iron states in patients with anemia. Conclusion: Patients with IDA can be differentiated from ACD and ACD/IDA but not ACD from ACD/IDA based on hepcidin‐25 alone. The combination of hepcidin‐25 with CHr in the hepcidin‐25 plot was useful for the differentiation of the states above.     

Haematologic data,iron parameters and molecular findings in two new cases of iron‐refractory iron deficiency anaemia

Matriptase‐2 (Tmprss6), a type II transmembrane serine protease, has an essential role in iron homoeostasis as a hepcidin regulator. Recently, patients with TMPRSS6 mutations and suffering from iron‐refractory iron deficiency anaemia (IRIDA) have been reported. We describe two new cases of IRIDA, one patient of Swiss origin and the second of Italian origin. The first case results from a large deletion of 1054 nucleotides corresponding to an in frame deletion of 30 amino acid residues in the low‐density lipoprotein receptor‐1/‐2 (LDLR‐1/‐2) domains and from a missense mutation in CUB1 (S304L). In the second case, a homozygous G→C mutation in the last nucleotide of exon 15 and which modified the consensus sequence of the 5′ splice donor site of intron 15 (AGgt→ACgt) was identified. Both patients had a high hepcidin level and low serum iron and transferrin saturation compared to age‐matched controls. Continuous perfusion of i.v. iron 4 h/d × 5 d in the first case resulted in a significant rise in haemoglobin. These new cases of IRIDA illustrate the importance of LDLR‐1/‐2 and CUB1 domains in matriptase‐2 function as well as the role of matriptase‐2 in hepcidin regulation. Furthermore a deletional form of TMPRSS6 (in LDLR‐1/‐2 domains) resulting in IRIDA is described for the first time. These cases reinforce the belief that patients suffering from IRIDA have no specific geographical or ethnic distribution and are sporadic secondary to different mutations of the matriptase‐2 gene.     

An inappropriate erythropoietic response to iron deficiency anaemia in the elderly

Summary This study was carried out to clarify the features of iron deficiency anaemia in the elderly. Subjects were chosen from residents undergoing an annual health check in a home for the aged and the features of anaemia in the elderly were compared with those in middle-aged adults under 60 years old. The red cell count, red cell size and haemoglobin content in an elderly group with iron-deficiency anaemia did not differ from those in middle-aged adults. No significant differences of the serum ferritin and iron levels were noted between the two groups. Total iron binding capacity was higher in the middle-aged adults than in the elderly, while the reticulocyte count was significantly lower in the elderly group. Immature reticulocytes showing a considerable amount of residual RNA by flow cytometry with fluorescent staining were also lower in the elderly group than in the middle-aged adults. Serum erythropoietin levels in both groups were significantly higher than in non-anaemic age-matched controls and no difference in erythropoietin levels was noted between them. The ratio of the reticulocyte count to the log-transformed erythropoietin level was low in the elderly group with iron-deficiency anaemia compared with the middle-aged adults with iron deficiency anaemia. The same result was seen when the immature reticulocyte count was related to the log-transformed erythropoietin level. These findings suggest that the red cell production response to erythropoietin in the elderly with iron-deficiency anaemia might be inappropriate compared with both non-anaemic and anaemic middle-aged adults.     

Reticulocyte haemoglobin content vs. soluble transferrin receptor and ferritin index in iron deficiency anaemia accompanied with inflammation

Ferritin concentration, as a parameter of iron status that is commonly used in the diagnosis of iron deficiency anaemia (IDA), often has limited values if the iron deficiency is accompanied by inflammatory disease. This study evaluated the value of reticulocyte haemoglobin content (CHr) and soluble transferrin receptor-ferritin index (sTfR/F) in the diagnosis of IDA and differential diagnosis of IDA and anaemia of chronic disease. The study included 66 nonanaemic individuals as controls, 86 patients with IDA divided into noninflammatory and inflammatory subgroups, and 32 patients with anaemia of chronic disease. Blood count, iron, transferrin saturation, total iron binding capacity, ferritin, C-reactive protein, sTfR and CHr were determined. Receiver operator characteristic curve analysis showed very high discriminating power for CHr, soluble transferrin receptor (sTfR) and sTfR/F in the diagnosis of IDA. In patients with anaemia of chronic disease these parameters showed no significant difference from the control. CHr and sTfR enabled recognition of iron deficiency and were not affected by acute phase reaction. They are sensitive markers of body iron status with additional value to conventional tests for the detection of iron deficiency.     

The links of hepcidin and erythropoietin in the interplay of inflammation and iron deficiency in a large observational study of rheumatoid arthritis

Anaemia affects quality of life and radiographic outcome in rheumatoid arthritis (RA). In a cross-sectional study with 779 patients, we assessed the prognostic potential of the major haematopoietic regulators, hepcidin and erythropoietin, comparing their serum concentrations with respect to different anaemia types, inflammatory activity, anti-cytokine-specific treatment effects and iron deficiency (ID) indices. The results showed that clinical disease activity was more closely associated with haemoglobin levels than with anti-tumour necrosis factor-alpha or interleukin 6 receptor effects. In ID, hepcidin was suppressed, independently of inflammation. Erythropoietin levels were inappropriately low in relation to the degree of anaemia, but, in contrast to low haemoglobin, not directly associated with joint damage progression. Hepcidin and erythropoietin levels are intimately connected with inflammation and ID. Interventional studies on these important targets are already in progress.     

The role of serum ferritin in the diagnosis of iron deficiency anaemia in patients with liver cirrhosis

Intragumtornchai T, Rojnukkarin P, Swasdikul D, Israsena S (Division of Haematology, and Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand). The role of serum ferritin in the diagnosis of iron deficiency anaemia in patients with liver cirrhosis. J Intern Med 1998; 243 : 233–41.

Objectives

.To determine the diagnostic values of serum ferritin and other conventional laboratory tests in the diagnosis of iron deficiency anaemia in patients with liver cirrhosis.

Design

.Cross-sectional study for diagnostic tests.

Setting

.University hospital.

Subjects

.Seventy-two consecutive patients with liver cirrhosis in whom the haemoglobin level was less than 13.0 g dL^?1 for men and 12.0 g dL^?1 for women. The diagnosis of liver cirrhosis was based on characteristic clinical and hepatic ultrasonographic findings.

Main outcome measures

.By using absence of bone marrow iron as the standard criterion, the diagnostic powers of mean corpuscular volume, transferrin saturation, serum ferritin and the presence of hypochromic red cells in the diagnosis of iron deficiency were compared by analysing the likelihood ratios, the area under the receiver operating curves (ROC) and the stepwise logistic regression associated with each test.

Results.<

> Twenty-nine patients (40.3%) demonstrated no stainable iron in the bone marrow. The likelihood ratios, the area under the ROC and the stepwise logistic regression indicated that serum ferritin was the most powerful test predictive of iron deficiency. Other tests added little further diagnostic values. The likelihood ratios associated with the serum ferritin levels were as follows: <50 μg L^?1, 22.3; 51–200 μg L^?1, 1.5–1.8; 201–400 μg L^?1, 1.0; > 400 μg L^?1, <1. These results indicate that serum ferritin level <50 μg L^?1 depict a very high probability of iron deficiency anaemia (0.83–0.99) irrespective of the patient's pre-test probability.

Conclusion

.Serum ferritin is the most powerful non-invasive test for the diagnosis of iron deficiency anaemia in patients with liver cirrhosis. It should be the primary test of choice in patients suspected of having the disease. When the level was less than 50 μg L^?1, iron supplement may be prescribed without necessitating bone marrow aspiration.

     

Prediction of iron deficiency in chronic inflammatory rheumatic disease anaemia

Summary. We prospectively studied 45 anaemic patients (3 7 women, 8 men) with chronic inflammatory rheumatic diseases. The combination of serum ferritin and CRP (as well as ESR) in its predictive capacity for bone marrow iron stores was examined. The relationship between other iron-related measurements (transferrin, transferrin saturation, soluble transferrin receptor, erythrocyte porphyrins and percentage of hypochromic/microcytic erythrocytes) and bone marrow iron stores was also investigated. Stainable bone marrow iron was taken as the most suitable standard to separate iron-deficient from iron-replete patients. 14 patients (31%) were lacking bone marrow iron. Regression analysis showed a good correlation between ferritin and bone marrow iron (adjusted R ²=0.721, P<00001). The combination of ferritin and CRP (ESR) did not improve the predictive power for bone marrow iron (adjusted R ²=0.715) in this cohort of patients with low systemic inflammatory activity. With respect to the bone marrow iron content the best predictive cut-off value of ferritin was 30μg/l (86% sensitivity, 90% specificity). The other iron-related parameters both individually and when combined were less powerful in predicting bone marrow iron than ferritin alone. Only zinc bound erythrocyte protoporphyrin in combination with ferritin slightly improved prediction (adjusted R ²=0.731). A cut-off point of 11% hypochromic erythrocytes reached a high specificity (90%), but was less sensitive (77%).     

A comparison between intravenous iron polymaltose complex (Ferrum Hausmann®) and oral ferrous fumarate in the treatment of iron deficiency anaemia in pregnancy

Abstract: Anaemia is the most common medical disorder in pregnancy with iron deficiency anaemia accounting for the majority of cases. Over 90% of the iron deficiency anaemia is due to red cell iron deficiency associated with depleted iron stores and deficient intake. The two main modalities of treating iron deficiency anaemia are oral or parenteral iron. Ferrous Hausmann® (iron dextrin) is the latest iron preparation which can be used for intravenous parenteral administration as a total dose infusion. This study compares the efficacy of Ferrum Hausmann® with oral ferrous fumarate therapy in the treatment of iron deficiency anaemia in pregnancy. Our study shows that treatment with intravenous Ferrum Hausmann® (iron dextrin) resulted in a significantly better level and rate of increase of haemoglobin (p<0.001). Serum ferritin, which is the best indicator of iron stores, was significantly higher (p<0.001) in the intravenous group. Other indices of iron status such as serum iron, serum transferrin and zinc protoporphyrin also showed a significant improvement in the intravenous group compared to those given oral iron. The results suggest that intravenous iron as a total dose infusion is able to replenish iron stores more efficiently, completely and at a faster rate than oral iron therapy, thus providing the fuel for stimulation of full erythopoiesis compared to oral iron. There were also no reports of any adverse reactions with intravenous iron dextrin, whereas there were a considerable proportion of women on oral iron therapy who reported side effects. In conclusion, intravenous iron therapy with Ferrous Hausmann® (iron dextrin) is a suitable, effective and safe alternative to oral iron therapy in the treatment of iron deficiency anaemia in pregnancy.     

Endoscopic evaluation of significant gastrointestinal lesions in patients with iron deficiency with and without anaemia: a Korean Association for the Study of Intestinal Disease Study

Background: Although endoscopy is recommended for patients with iron deficiency anaemia, there is, currently, no consensus on the role of endoscopy for iron‐deficient patients without anaemia. The goal of this study was to determine the prevalence of serious gastrointestinal (GI) lesions, identified by endoscopy in patients with iron deficiency and anaemia compared with patients with iron deficiency without anaemia. Methods: One thousand five hundred and eighteen patients with a ferritin value of ≤50 ng/mL and a total iron‐binding capacity ≥300 mg/dL were retrospectively investigated using oesophagogastroduodenoscopy and colonoscopy between January 2005 and September 2006. The lesions identified were classified as clinically important according to standard predetermined criteria. Results: Among the 1518 cases, 749 patients had anaemia and 769 had normal haemoglobin levels. Clinically important lesions were identified in 24.6% of the patients with anaemia and in 22.8% of the patients without anaemia (P > 0.05). The frequency of lower GI tract lesions (13.6 vs 11.4%, P > 0.05) and upper GI tract lesions (11.9 vs 12.5%, P > 0.05) was similar in the comparisons between the two groups. However, the frequency of malignant GI lesions was higher in the patients with anaemia (5.1 vs 0.7%, P < 0.01). In addition, the patients without anaemia were significantly more likely to have early‐stage neoplasia (adenoma, early gastric cancer and Dukes’ A and B colon cancer) than were the patients with anaemia (98.4 vs 52.5%, P < 0.01). Conclusion: The results of this study suggest that patients with iron deficiency should undergo endoscopic evaluation of the GI tract, irrespective of whether they have anaemia. The endoscopic evaluation of the GI tract in patients with iron deficiency without anaemia could provide an opportunity for the detection of early‐stage neoplasia at a curable stage.