Severe iron deficiency anemia in transgenic mice expressing liver hepcidin

We recently reported the hemochromatosis-like phenotype observed in our Usf2 knockout mice. In these mice, as in murine models of hemochromatosis and patients with hereditary hemochromatosis, iron accumulates in parenchymal cells (in particular, liver and pancreas), whereas the reticuloendothelial system is spared from this iron loading. We suggested that this phenotypic trait could be attributed to the absence, in the Usf2 knockout mice, of a secreted liver-specific peptide, hepcidin. We conjectured that the reverse situation, namely overexpression of hepcidin, might result in phenotypic traits of iron deficiency. This question was addressed by generating transgenic mice expressing hepcidin under the control of the liver-specific transthyretin promoter. We found that the majority of the transgenic mice were born with a pale skin and died within a few hours after birth. These transgenic animals had decreased body iron levels and presented severe microcytic hypochromic anemia. So far, three mosaic transgenic animals have survived. They were unequivocally identified by physical features, including reduced body size, pallor, hairless and crumpled skin. These pleiotropic effects were found to be associated with erythrocyte abnormalities, with marked anisocytosis, poikylocytosis and hypochromia, which are features characteristic of iron-deficiency anemia. These results strongly support the proposed role of hepcidin as a putative iron-regulatory hormone. The animal models devoid of hepcidin (the Usf2 knockout mice) or overexpressing the peptide (the transgenic mice presented in this paper) represent valuable tools for investigating iron homeostasis in vivo and for deciphering the molecular mechanisms of hepcidin action.     

Tracheopathia osteoplastica associated with iron deficiency anemia

Tracheopathia osteoplastica (TPO) is a benign disease of trachea characterised by numerous cartilaginous or bony structures protruding into tracheobronchial lumen. We report a case of a 85-year-old male patient in whom tracheopathia osteoplastica was diagnosed incidentally during bronchoscopy which was missed on chest computed tomography examination. The patient also had iron deficiency anemia, the cause of which was not identified. We review TPO and discuss the associated abnormalities reported in the literature.     

Data-driven physiologic thresholds for iron deficiency associated with hematologic decline

Iron-deficiency contributes to a ∼50% of anemia prevalence worldwide, but reference intervals for iron status tests are not optimized for anemia diagnosis. To address this limitation, we identified the serum ferritin (SF) thresholds associated with hematologic decline in iron-deficient patients, and the SF thresholds from which an SF increase was associated with hematologic improvement. Paired red blood cell and SF measurements were analysed from two adult cohorts at Massachusetts General Hospital (MGH), from 2008-2011 (N = 48 409), and 2016-2018 (N = 10 042). Inter-patient measurements in the first cohort were used to define optimal SF thresholds based on the physiologic relationship between SF and red cell measurements. Intra-patient measurements (1-26 weeks apart) in the second cohort were used to identify SF thresholds from which an SF increase was associated, with an increase in red cell measurements. The identified optimal SF thresholds varied with age, sex and red cell measure. Thresholds associated with a ∼5% decline in red cell index were typically in the range 10-25 ng/mL. Thresholds for younger women (18-45 year) were ∼5 ng/mL lower than for older women (60-95 years), and ∼10 ng/mL lower than for men. Thresholds from which a subsequent increase in SF was associated with a concomitant increase in red cell measure showed similar patterns: younger women had lower thresholds (∼15 ng/mL) than older women (∼25 ng/mL), or men (∼35 ng/mL). These results suggest that diagnostic accuracy may be improved by setting different SF thresholds for younger women, older women, and men. This study illustrates how clinical databases may provide physiologic evidence for improved diagnostic thresholds.     

Is trichuriasis associated with iron deficiency anemia?

We performed quantitative fecal examinations, hemograms, and serum iron determinations on 103 first-grade children from Vieques Island, Puerto Rico, to determine whether trichuriasis was associated with iron deficiency and anemia. Although hemoglobin values tended to be slightly lower in Trichuris-infected children, there was no association between trichuriasis and serum iron or transferrin saturation values. These data demonstrate that in lightly infected children such as the population studied trichuriasis is not associated with iron deficiency anemia.     

慢性肾脏病5期患者血清铁调素表达水平及与维生素D的相关性研究

目的探讨血清铁调素(Hepcidin)在慢性肾脏病(chronic kidney disease,CKD)5期患者中的表达水平及与血清25羟维生素D[25(OH)D]的关系。方法入选CKD 5期患者85例,其中维持性血液透析(MHD组)55例,非透析组30例;健康体检者30名为对照组。检测三组血清Hepcidin、25(OH)D水平;MHD组、非透析组同时测定血红蛋白、钙、磷、甲状旁腺素(PTH)、血清铁蛋白(SF)、血清铁(SI)、转铁蛋白饱和度(TSAT)、C反应蛋白(CRP)、血肌酐(Scr)等临床指标,分析Hepcidin与25(OH)D等指标的相互关系。结果MHD组、非透析组、对照组Hepcidin水平分别是(91.8±11.3)μg/L、(58.9±5.27)μg/L、(46.9±5.95)μg/L;25(OH)D水平分别是(25.9±3.25)μg/L、(29.2±4.21)μg/L、(36.9±3.65)μg/L,组间比较,差异有统计学意义(P0.05)。85例患者中,28例25(OH)D缺乏,32例25(OH)D不足,25例25(OH)D正常。与25(OH)D正常组相比,缺乏组血清Hepcidin、CRP及不足组的PTH明显升高,两组血红蛋白明显降低,差异有统计学意义(P0.05)。相关性分析结果显示,CKD 5期患者血清Hepcidin水平与血红蛋白、SI、25(OH)D呈负相关(r=-0.436,P0.01;r=-0.337,P0.05;r=-0.578,P0.05),与SF、CRP呈正相关(r=0.406,P0.05;r=0.366,P0.05),与血钙、磷、PTH、SCr、白蛋白无相关性(P0.05)。多元线性回归分析Hepcidin与血红蛋白、CRP、SF相关(P0.05)。结论 CKD 5期患者Hepcidin表达水平升高,尤以MHD组明显;Hepcidin的表达水平与贫血、炎症及铁负荷状态密切相关;25(OH)D缺乏或不足在CKD 5期患者较为常见,25(OH)D缺乏患者血Hepcidin升高,但多元线性回归分析并未显示与Hepcidin具有相关性。     

Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease

The anemia of chronic disease is a prevalent, poorly understood condition that afflicts patients with a wide variety of diseases, including infections, malignancies, and rheumatologic disorders. It is characterized by a blunted erythropoietin response by erythroid precursors, decreased red blood cell survival, and a defect in iron absorption and macrophage iron retention, which interrupts iron delivery to erythroid precursor cells. We noted that patients with large hepatic adenomas had severe iron refractory anemia similar to that observed in anemia of chronic disease. This anemia resolved spontaneously after adenoma resection or liver transplantation. We investigated the role of the adenomas in the pathogenesis of the anemia and found that they produce inappropriately high levels of hepcidin mRNA. Hepcidin is a peptide hormone that has been implicated in controlling the release of iron from cells. We conclude that hepcidin plays a major, causative role in the anemia observed in our subgroup of patients with hepatic adenomas, and we speculate that it is important in the pathogenesis of the anemia of chronic disease in general.     

Regulation of iron metabolism through GDF15 and hepcidin in pyruvate kinase deficiency

Iron absorption is inadequately increased in patients with chronic haemolytic anaemia, which is commonly complicated by iron overload. Growth differentiation factor 15 (GDF15) has been identified as a bone marrow-derived factor that abrogates hepcidin-mediated protection from iron overload under conditions of increased erythropoiesis. Increased concentrations of GDF15 have been reported in β-thalassaemia patients and GDF15 has been found to suppress hepcidin expression in vitro . To further study the interdependencies of iron metabolism and erythropoiesis in vivo , the concentrations of hepcidin and GDF15 were determined in sera from 22 patients with pyruvate kinase deficiency (PKD) and 21 healthy control subjects. In PKD patients, serum hepcidin levels were 13-fold lower than in controls (2·0 ng/ml vs. 26·2 ng/ml) and GDF15 was significantly higher (859 pg/ml vs. 528 pg/ml). Serum hepcidin concentrations correlated positively with haemoglobin and negatively with serum GDF15. These results suggest that GDF15 contributes to low hepcidin expression and iron loading in PKD.     

Serum selenium status in children with iron deficiency anemia.

Serum selenium concentration was investigated in 40 children with iron deficiency anemia and in 40 control subjects matched for age, sex and geographical origin. A spectrofluorometric method was used for determination of the selenium level. It was found to be significantly lower (p < 0.001) in the patient group, which consisted of both normally developed and malnourished children. Patients also having pica had higher levels of selenium compared to patients without pica. There was no relation between the serum selenium concentration and hematological parameters such as hemoglobin, serum iron, serum iron binding capacity and unsaturated iron binding capacity. However the results of 15 patients followed during iron therapy indicated that the duration of the anemic period may affect the selenium concentration. This study also suggests the effectiveness of iron and selenium administration.     

Serum hepcidin as a diagnostic test of iron deficiency in premenopausal female blood donors

Background

Currently used indicators of iron status have limitations. Hepcidin, a key regulator of iron metabolism, is reduced in iron deficiency. We sought to determine the properties of hepcidin as a diagnostic test of iron deficiency.

Design and Methods

Sera from female, non-anemic, whole blood donors were analyzed for hepcidin (enzyme-linked immunosorbent assay), ferritin, soluble transferrin receptor and C-reactive protein. Iron deficiency was defined as (i) serum ferritin less than 15 ng/mL or (ii) soluble transferrin receptor /log(ferritin) index greater than 3.2 if the C-reactive protein concentration was less than 10 mg/L, or greater than 2.2 if the C-reactive protein concentration was greater than 10 mg/L). Receiver operating characteristic curves were plotted to determine the overall utility and identify optimal cut-points of hepcidin as a test of iron deficiency.

Results

In 261 blood donors the prevalence of iron deficiency defined by ferritin concentration was 59/261 [22.6% (17.5, 27.7)], whereas defined by soluble transferrin receptor/log(ferritin) index it was 53/261 [20.4% (15.4, 25.2)]. The 95% reference range of hepcidin concentration in the iron-replete population was 8.2–199.7 ng/mL. The area under the receiver operating characteristic curve for hepcidin compared with ferritin concentration less than 15 ng/mL was 0.87 (0.82, 0.92), while that compared with the soluble transferrin receptor /log(ferritin) index was 0.89 (95% CI 0.84, 0.93). For a diagnosis of iron deficiency defined by the soluble transferrin receptor/log(ferritin) index, hepcidin less than 8 ng/mL had a sensitivity of 41.5% and a specificity of 97.6%, while hepcidin less than 18 ng/mL had a sensitivity of 79.2% and a specificity of 85.6%.

Conclusions

Serum hepcidin concentration may be a useful indicator of deficient iron stores. Further studies are required to evaluate the role of hepcidin in the diagnosis of iron deficiency in other groups of patients.     

Treatment of iron deficiency anemia associated with gastrointestinal tract diseases

The gastrointestinal (GI) tract is a common site of bleeding that may lead to iron deficiency anemia (IDA). Treatment of IDA depends on severity and acuity of patients’ signs and symptoms. While red blood cell transfusions may be required in hemodynamically unstable patients, transfusions should be avoided in chronically anemic patients due to their potential side effects and cost. Iron studies need to be performed after episodes of GI bleeding and stores need to be replenished before anemia develops. Oral ...     

Maternal serum hepcidin is low at term and independent of cord blood iron status

Objectives: Hepcidin is the key regulator of iron homeostasis. The aims of this study were to determine serum hepcidin concentrations and reference ranges in pregnant women and cord blood of newborns at term and to evaluate the associations between hepcidin concentrations and iron status parameters. Methods: A total of 191 pregnant women–newborn pairs were studied in Kuopio University Hospital, Finland. The measured parameters were serum hepcidin, ferritin, transferrin receptor, transferrin saturation, red cell indices, and erythropoietin. Results: The hepcidin concentration in pregnant women was significantly lower than in cord blood at term [geometric mean concentration (GMC) (95% confidence intervals) in pregnant women 10.7 ng/mL (8.5–13.4 ng/mL) vs. GMC of cord blood hepcidin 69.3 ng/mL (55.3–86.8 ng/mL), P < 0.001, adjusted analysis of variance]. Hepcidin was undetectable in 12% of mothers. Hepcidin concentration in pregnant women was the lowest in those who had the lowest iron status. However, maternal hepcidin concentration was not associated with cord blood hepcidin or iron status markers. Hepcidin concentration in cord blood was associated with cord blood iron status, but not with maternal iron status. Conclusions: At term pregnancy, hepcidin concentrations are very low, allowing maximal availability of iron for the fetus. Maternal and cord blood hepcidin levels were independently associated with either maternal or cord blood iron status.     

Dysmetabolic hyperferritinemia is associated with normal transferrin saturation,mild hepatic iron overload,and elevated hepcidin

Hyperferritinemia is common in individuals with the metabolic syndrome (dysmetabolic hyperferritinemia), but its pathophysiology and the degree to which it reflects tissue iron overload remains unclear. We conducted a cross-sectional study evaluating ten cases with dysmetabolic hyperferritinemia for liver iron overload and compared their serum iron indices and urine hepcidin levels to healthy controls. Seven out of ten cases had mild hepatic iron overload by magnetic resonance imaging (MRI) (median, 75 μmol/g dry weight). Cases had higher serum ferritin than controls (median, 672 μg/L vs. 105 μg/L, p < 0.001), but the median transferrin saturation was not significantly different (38% vs. 36%, p = 0.5). Urinary hepcidin was elevated in dysmetabolic hyperferritinemia (median; 1,584 ng/mg of creatinine vs. 799 ng/mg of creatinine, p = 0.05). Dysmetabolic hyperferritinemia is characterized by hyperferritinemia with normal transferrin saturation, elevated hepcidin levels, and mild liver iron overload in a subset of patients.     

Severe thrombocytosis and leukocytosis associated with iron deficiency anaemia: a case-report

Reactive thrombocytosis (secondary thrombocytosis) is frequent and typically moderate. We report a case of extreme thrombocytosis and leukocytosis secondary to an iron deficiency anemia. A 21-year-old woman is admitted in emergency department for acute headache. Biological assessment reveals a severe microcytic anaemia (5.4 g/dL) with thrombocytosis (2500 giga/L) and leukocytosis (35 giga/L) leading to multiple diagnosis hypotheses. Finally, biological evaluation concludes to a diagnosis of iron deficiency anaemia related to insufficient oral intake and menorrhagia. Reactive hyperleukocytosis and thrombocytosis rapidly resolved with iron supplementation. This case is a reminder that iron deficiency-related thrombocytosis can sometimes be severe. However, the associated reactive leukocytosis is quite exceptional.     

Carbonyl iron therapy for iron deficiency anemia

To determine if elemental carbonyl iron powder is safe and effective therapy for iron deficiency anemia, 20 nonanemic and 32 anemic volunteers were studied. Single doses of 1,000 to 10,000 mg of carbonyl iron (15 to 150 times the 65 mg of iron in the usual dose of ferrous sulfate) were tolerated by nonanemic volunteers with no evidence of toxicity and only minor gastrointestinal side effects. Anemic volunteers (menstruating women who had previously donated blood) were treated with several regimens providing 1,000 to 3,000 mg of carbonyl iron daily in one to three doses for 8 to 28 days. After 12 weeks anemia was corrected in 29 of 32 patients, and serum ferritin was greater than 12 micrograms/L in 14. Hemoglobin regeneration proceeded at a rate similar to that described for therapy with oral iron salts and parenteral iron dextran. There was no evidence of hematologic, hepatic, or renal toxicity, but mild gastrointestinal side effects occurred in a majority of anemic volunteers. Carbonyl iron is an effective, inexpensive treatment for iron deficiency anemia, is accompanied by tolerable side effects and may have an advantage over therapy with iron salts by substantially reducing or eliminating the risk of iron poisoning in children.